Home Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
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Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer

  • Guorong Yao ORCID logo EMAIL logo , Kaiyue Zhao , Kaikai Bao and Jing Li
Published/Copyright: February 17, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

Background

Radiotherapy-associated secondary cancer is an important issue for the treatment of breast cancer (BCa). This study aimed to investigate the molecular mechanism and genetic risk factors for radiation-associated secondary diseases in BCa.

Methods

The differentially expressed genes (DEGs) between preradiation and postradiation BCa samples in the GSE65505 dataset were obtained. The pathways related to the radiation-associated DEGs in the protein–protein interaction (PPI) network modules were identified. miRNAs targeted to the key genes in the PPI network were identified, and their association with BCa prognosis was analyzed.

Results

A total of 136 radiation-associated DEGs preradiation and postradiation BCa samples were screened out. The PPI network consisted of a significant module that consisted of 21 upregulated DEGs that were associated with “hsa04512: ECM–receptor interaction,” “hsa04151: PI3K-Akt signaling pathway,” and “hsa04115: p53 signaling pathway.” Sixteen DEGs, including three collagen genes collagen type I alpha 1 chain (COL1A1), COL3A1, and COL1A2, were enriched in 17 radiation-associated pathways. The three genes were upregulated in BCa tissues compared with controls and were also elevated by radiation. They were targeted by hsa-miR-29a/c, and the expression levels of hsa-miR-29a/c were associated with a poor prognosis of BCa.

Conclusions

The upregulation of COL1A1, COL3A1, and COL1A2 might be genetic risk factors for radiation-associated secondary diseases in BCa.

Keywords: radiotherapy; secondary cancer; breast cancer; Type I collagen; Type III collagen

1 Introduction

Breast cancer (BCa) is the most commonly diagnosed malignant cancer and the leading cause of cancer-related premature mortality in women worldwide [1]. About 2.1 million newly diagnosed cases of BCa were estimated in 2018 [1]. Epidemiologic studies have well established a series of risk factors for BCa, including family history, race, physical inactivity, obesity, genetic variants, and instability [2,3]. However, the treatment of BCa is still an important issue due to the high recurrence and mortality of this disease.

Adjuvant radiotherapy is the standard treatment for BCa patients that are undergoing breast-conservation surgery or mastectomy. Radiotherapy reduces BCa recurrence and death significantly [4,5,6]. Overall, radiotherapy reduces the 10 year risk of first recurrence from 35.0 to 19.3% and decreases the 15 year risk of death from 25.2 to 21.4% [4]. However, there are increasing evidence showing that radiotherapy causes secondary cancers and heart diseases decades later [7,8,9,10]. For instance, patients exposed to radiotherapy for prostate cancer and BCa had an over-time increased risk of bladder, colorectal, lung, and thyroid cancers compared with patients unexposed to radiotherapy [8,10]. In addition, the chest wall symptoms in BCa patients exposed to radiotherapy were worse than that of patients unexposed to radiotherapy [9]. Hodgkin lymphoma patients that were treated with chest radiotherapy have a high risk of BCa [11]. However, the molecular mechanisms of the pathogenesis of radiation-associated secondary cancers are not clear until now.

Research has pointed out that the smoking habit is a risk factor for radiation-associated secondary primary cancer [12]. In addition, there is evidence showing genetic susceptibility to radiation-associated secondary BCa [11]. Hodgkin lymphoma patients that had a high risk of radiation-associated secondary BCa had a higher polygenic risk score that was composed of the features of nine single-nucleotide polymorphisms [11]. For radiation-associated secondary cancers in patients with BCa, however, the molecular mechanism has not been reported until now.

For filling this gap, we performed this study to identify the radiation-associated genes in BCa. The identification of radiation-related genetic susceptibility and genetic risk factors would be of great value for better understanding the molecular mechanisms underlying the radiation-associated secondary cancers in patients with BCa.

2 Materials and methods

2.1 Microarray data

The mRNA expression dataset GSE65505 was downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/). GSE65505 (GPL17586 platform, [HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version]) consisted of 62 BCa tumor samples, including 29 paired preradiation and postradiation tumor samples: 6, 8, and 15 patients treated with 15 Gy, 18 Gy, and 21 Gy intensity-modulated radiotherapy. BCa samples were extracted from women (aged >55 years old) that had clinically node negative, estrogen receptors (ER)+ and/or PR+, Human epidermal growth factor receptor-2 (HER2−), T1 invasive carcinomas or low-intermediate grade in situ disease (≤2 cm).

2.2 Data processing and identification of radiation-associated genes

The series matrix files from paired preradiation and postradiation tumor samples (n = 58) were downloaded and preprocessed using the Limma package (version 3.34.0; https://bioconductor.org/packages/release/bioc/html/limma.html). Then the differentially expressed genes (DEGs) between paired preradiation and postradiation tumor samples were identified using the Limma package with the criteria of p < 0.05 and |log2(fold change, FC)| ≥ 0.585 (|FC| ≥ 1.5). The sample hierarchical clustering analysis was performed for DEGs using the pheatmap package (version 1.0.8; https://cran.r-project.org/package=pheatmap). The genes common to 15, 18, and 21 Gy radiotherapy-induced DEGs were identified using the Venn diagram analysis and were regarded as radiation-associated genes in BCa.

2.3 Enrichment analysis of radiation-associated genes

To illuminate the radiation-induced molecular functional changes in BCa, the Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were associated with the radiation-associated genes DEGs were identified. Functional enrichment analysis was performed using the clusterprofiler package (https://github.com/GuangchuangYu/clusterProfiler). The threshold for selecting the significant biological processes and pathways were set at adjusted p value <0.05 and gene count ≥2.

2.4 Construction of protein–protein interaction network (PPI) of radiation-associated DEGs

The interactions between the products of radiation-associated DEGs in the GSE65505 dataset were predicted in the STRING database (Version: 10.0, http://www.string-db.org/) with the default parameter (score >0.4). Then the PPI network of radiation-associated genes was constructed using the Cytoscape software (version 3.4.0, http://chianti.ucsd.edu/cytoscape-3.4.0/). The important module in the PPI network (score >5) was identified using the MCODE plugin in Cytoscape. Radiation-associated genes that were included in the important modules were subjected to the functional enrichment analysis using the clusterprofiler package. The significant pathways that were associated with the genes in important module were selected using the same criteria as mentioned above.

2.5 Identification of BCa-associated pathways

To select the key pathways related to the radiation-associated DEGs in the important module, the BCa-associated pathways in Comparative Toxicogenomics Database (CTD, http://ctdbase.org/) were identified using the searching term of “breast neoplasm.” The items overlapped between the CTD database and the KEGG pathways were regarded as the key pathways in BCa, and the enriched genes were regarded as the key radiation-associated DEGs in BCa.

2.6 Construction of miRNA–target network

The miRNA–target pairs of the aforementioned key radiation-associated DEGs in BCa were predicted using the Webgestal online tool [13] using the overrepresentation enrichment analysis methods. Then the miRNA–target pairs with the p value of less than 0.05 were selected and used for the construction of miRNA–target network. The network was visualized using the Cytoscape software.

2.7 Identification of prognosis-associated genes and miRNAs in BCa

To investigate the association of genes and miRNAs with the prognosis of BCa, the correlation of aforementioned radiation-associated genes and miRNAs in the miRNA–target network with the overall survival (OS) of patients with breast invasive carcinoma (BRCA) in the Cancer Genome Atlas (TCGA) were analyzed using the user-friendly and interactive web resource of UALCAN (http://ualcan.path.uab.edu/index.html). Significantly difference was identified using the criterion of logRank p < 0.05.

3 Results

3.1 Identification of radiation-associated genes in BCa in GSE65505

A total of 405, 204, and 325 DEGs were identified in BCa tumor samples receiving 15 Gy, 18 Gy, and 21 Gy intensity-modulated radiotherapy in the GSE65505 dataset, respectively (Figure 1a). Hierarchical clustering analysis demonstrated the distinct expression profiles of these DEGs in samples preradiation and postradiation (Figure 1b). Venn diagram analysis showed that common 133 DEGs were upregulated by the three radiotherapies, and only three DEGs were commonly downregulated (Figure 1c). Then, 136 radiation-associated DEGs in BCa were identified in this study (Table A1).

Figure 1 The statistics and clustering of the DEGs in BCa preradiation and postradiation: (a) the volcano plot of the DEGs in BCa samples between preradiotherapy and postradiotherapy (15 Gy, 18 Gy, and 21 Gy), (b) the hierarchical clustering analysis of DEGs, and (c) the Venn diagram of the upregulated and downregulated radiation-associated genes in BCa in the GSE65505 dataset.
Figure 1

The statistics and clustering of the DEGs in BCa preradiation and postradiation: (a) the volcano plot of the DEGs in BCa samples between preradiotherapy and postradiotherapy (15 Gy, 18 Gy, and 21 Gy), (b) the hierarchical clustering analysis of DEGs, and (c) the Venn diagram of the upregulated and downregulated radiation-associated genes in BCa in the GSE65505 dataset.

3.2 Enrichment analysis of upregulated radiation-associated DEGs in BCa

The functional enrichment analysis of the 136 radiation-associated DEGs indicated that these genes were enriched into 563 biological processes that were associated with extracellular matrix (ECM) organization, inflammatory response, response to metal ion, neutrophil-mediated immunity, and cell chemotaxis, and 38 KEGG pathways including advanced glycation end-receptor for dvanced glycation end products (AGE-RAGE) signaling pathway in diabetic complication, p53 signaling pathway, PI3K-Akt signaling pathway, and ECM–receptor interaction. The top ten biological processes and KEGG pathways are shown in Table A2.

3.3 PPI network of radiation-associated DEGs in BCa

The PPI network that derived from the 136 radiation-associated genes was composed of 112 nodes (products of genes) and 529 lines (interaction pairs; Figure 2a). One module of a score of 9.9 and 21 upregulated radiation-associated DEGs was identified from the PPI network (Figure 2b). The interaction degree of these nodes is shown in Table 1. The insulin like growth factor 1 (IGF1), matrix metallopeptidase 2 (MMP2), collagen type I alpha 1 chain (COL1A1), COL1A2, and COL3A1 gene had the interaction degrees of 30, 27, 22, 18, and 16, respectively.

Figure 2 The PPI network and the important module of the radiation-associated genes in BCa: (a) the PPI network consisted of 111 upregulated and 1 downregulated radiation-associated genes in BCa and (b) the important module (score = 9.9, 21 nodes) identified using MCODE. Node size indicates the interaction degree. The higher the degree, the larger the node size is. The one downregulated radiation-associated gene is presented by blue square.
Figure 2

The PPI network and the important module of the radiation-associated genes in BCa: (a) the PPI network consisted of 111 upregulated and 1 downregulated radiation-associated genes in BCa and (b) the important module (score = 9.9, 21 nodes) identified using MCODE. Node size indicates the interaction degree. The higher the degree, the larger the node size is. The one downregulated radiation-associated gene is presented by blue square.

Table 1

The list and interaction degree of the 21 upregulated radiation-associated genes in the module of the PPI network of breast cancer

Nodes Regulation Degree Nodes Regulation Degree
CCL2 UP 33 DUSP1 UP 18
TIMP1 UP 30 COL3A1 UP 16
IGF1 UP 30 VWF UP 16
MMP2 UP 27 BTG2 UP 13
COL1A1 UP 22 NFKBIA UP 13
CD68 UP 22 THBS2 UP 12
SERPINE1 UP 22 NR4A1 UP 12
EGR1 UP 21 JUNB UP 11
ATF3 UP 21 ZFP36 UP 10
THBS1 UP 19 FOSB UP 9
COL1A2 UP 18

CCL2: C-C motif chemokine ligand 2; MMP2: matrix metallopeptidase 2; COL1A1: collagen type I alpha 1 Chain; SERPINE1: serpin family E member 1; EGR1: early growth response 1; COL3A1: collagen type III alpha 1 chain; THBS1: thrombospondin 1; VWF: von Willebrand factor; THBS2: thrombospondin 2; NFKBIA: nuclear factor kappa B inhibitor alpha; FOSB: FosB proto-oncogene, AP-1 transcription factor subunit; DUSP1: dual specificity phosphatase 1.

3.4 Pathways that related to radiation-associated genes

The 21 upregulated radiation-associated DEGs in the module were associated with 19 KEGG pathways such as “hsa04933: AGE-RAGE signaling pathway in diabetic complications,” “hsa04512: ECM–receptor interaction,” “hsa04151: PI3K-Akt signaling pathway,” and “hsa04115: p53 signaling pathway” (Table 2). The function properties of the 21 radiation-associated genes were basically in line with the 136 radiation-associated DEGs in BCa. Among the 19 pathways, 17 pathways that were common to BCa-related pathways in the CTD database were regarded as the key radiation-associated pathways in BCa. Moreover, 16 upregulated radiation-associated DEGs (including IGF1, MMP2, COL1A1, COL3A1, and ZFP36) were involved in the 17 key radiation-associated pathways (Table 2).

Table 2

The list of top 10 biological processes and KEGG pathways related to the radiation-associated genes in the module of the PPI network of breast cancer

ID Description Count p value p. adjust Gene symbol
*hsa04933 AGE-RAGE signaling pathway in diabetic complications 7 2.53 × 10−9 2.71 × 10−7 CCL2, MMP2, COL1A1, SERPINE1, EGR1, COL1A2, and COL3A1
*hsa04512 ECM–receptor interaction 5 1.91 × 10−6 1.02 × 10−4 COL1A1, THBS1, COL1A2, VWF, and THBS2
*hsa04510 Focal adhesion 6 6.19 × 10−6 2.21 × 10−4 IGF1, COL1A1, THBS1, COL1A2, VWF, and THBS2
hsa04926 Relaxin signaling pathway 5 1.26 × 10−5 3.05 × 10−4 MMP2, COL1A1, COL1A2, COL3A1, and NFKBIA
*hsa04151 PI3K-Akt signaling pathway 7 1.43 × 10−5 3.05 × 10−4 IGF1, COL1A1, THBS1, COL1A2, VWF, THBS2, and NR4A1
*hsa05205 Proteoglycans in cancer 5 1.17 × 10−4 2.08 × 10−3 IGF1, MMP2, COL1A1, THBS1, and COL1A2
*hsa04611 Platelet activation 4 2.16 × 10−4 3.20 × 10−3 COL1A1, COL1A2, COL3A1, and VWF
*hsa05144 Malaria 3 2.40 × 10−4 3.20 × 10−3 CCL2, THBS1, and THBS2
*hsa04115 p53 signaling pathway 3 7.04 × 10−4 8.37 × 10−3 IGF1, SERPINE1, and THBS1
hsa05165 Human papillomavirus infection 5 1.05 × 10-3 1.13 × 10-2 COL1A1, THBS1, COL1A2, VWF, and THBS2
*hsa04657 IL-17 signaling pathway 3 1.53 × 10−3 1.40 × 10−2 CCL2, NFKBIA, and FOSB
*hsa04974 Protein digestion and absorption 3 1.58 × 10−3 1.40 × 10−2 COL1A1, COL1A2, and COL3A1
*hsa05142 Chagas disease (American trypanosomiasis) 3 1.93 × 10−3 1.48 × 10−2 CCL2, SERPINE1, and NFKBIA
*hsa05146 Amoebiasis 3 1.93 × 10−3 1.48 × 10−2 COL1A1, COL1A2, and COL3A1
*hsa04066 HIF-1 signaling pathway 3 2.34 × 10−3 1.67 × 10−2 TIMP1, IGF1, and SERPINE1
*hsa04668 TNF signaling pathway 3 2.53 × 10−3 1.69 × 10−2 CCL2, NFKBIA, and JUNB
*hsa04380 Osteoclast differentiation 3 3.69 × 10−3 2.32 × 10−2 NFKBIA, JUNB, and FOSB
*hsa05219 Bladder cancer 2 4.55 × 10−3 2.62 × 10−2 MMP2 and THBS1
*hsa05418 Fluid shear stress and atherosclerosis 3 4.65 × 10−3 2.62 × 10−2 CCL2, MMP2, and DUSP1

*Notes the overlapping KEGG pathways between the comparative toxicogenomics database and that related to the 21 radiation-sensitive genes.

3.5 Construction of the radiation-associated miRNA–target network in BCa

The miRNA–target pairs of the aforementioned 16 radiation-associated DEGs in BCa were predicted, and the corresponding radiation-associated miRNA–target network was constructed (Figure 3). This miRNA–target network consisted of ten radiation-associated DEGs, including IGF1, MMP2, COL1A1, COL3A1, and ZFP36, and nine miRNAs, including hsa-miR-29a, hsa-miR-29b, hsa-miR-29c, hsa-miR-196a, and hsa-miR-196b. In this network, five radiation-associated DEGs, including IGF1, MMP2, COL1A1, COL3A1, and ZFP36, were simultaneously regulated by hsa-miR-29a, hsa-miR-29b, and hsa-miR-29c. hsa-miR-196a and hsa-miR-196b both targeted to three collagen genes, including COL1A1, COL3A1, and COL1A2. The other four radiation-associated DEGs, including JunB proto-oncogene (JUNB), BTG antiproliferation factor 2 (BTG2), FosB proto-oncogene, AP-1 transcription factor subunit (FOSB), and nuclear receptor subfamily 4 group A member 1 (NR4A1), were regulated by one or two miRNAs, respectively (Figure 3).

Figure 3 The miRNA–target regulatory network involving the radiation-associated genes in the key pathways related to BCa. Node size indicates the interaction degree. The higher the degree, the larger the node size is. The miRNA–target interaction pairs were identified using the Webgestal online tool. The miRNA–target pairs with a p < 0.05 are used for the construction of the miRNA–target network.
Figure 3

The miRNA–target regulatory network involving the radiation-associated genes in the key pathways related to BCa. Node size indicates the interaction degree. The higher the degree, the larger the node size is. The miRNA–target interaction pairs were identified using the Webgestal online tool. The miRNA–target pairs with a p < 0.05 are used for the construction of the miRNA–target network.

3.6 The association of radiation-associated genes with the prognosis of BCa

Based on the analysis in the UALCAN database, we found that two genes, BTG2 and JUNB, and four miRNAs, including hsa-miR-29a, hsa-miR-29c, hsa-miR-224, and hsa-miR-196b, were significantly associated with the prognosis in BCa (Figure 4). The high expression levels of JUNB (p = 0.031), BTG2 (p = 0.019), hsa-miR-29a (p = 0.0058), and hsa-miR-29c (p = 0.014) as well as the low expression levels of hsa-miR-224 (p = 0.033) and hsa-miR-196b (p = 0.051) were associated with a low survival probability in the TCGA BRCA patients (Figure 4).

Figure 4 The survival analysis of genes and miRNAs in the miRNA–target regulatory network. Survival analysis was performed using the UALCAN online tool and based on the TCGA cohort (breast invasive carcinoma).
Figure 4

The survival analysis of genes and miRNAs in the miRNA–target regulatory network. Survival analysis was performed using the UALCAN online tool and based on the TCGA cohort (breast invasive carcinoma).

Besides, we found three genes, including COL1A1, COL3A1, and COL1A2, were significantly upregulated in TCGA BRCA tumor samples compared with normal controls (Figure 5), whereas the other seven genes were not significantly changed in BCa tumor samples (data now shown).

Figure 5 The expression of the COL1A1, COL3A1, and COL1A2 genes in the TCGA breast cancer tumor and normal control samples. The statistical differences were analyzed using the UALCAN online tool. Data was expressed as median and range (minimum to maximum).
Figure 5

The expression of the COL1A1, COL3A1, and COL1A2 genes in the TCGA breast cancer tumor and normal control samples. The statistical differences were analyzed using the UALCAN online tool. Data was expressed as median and range (minimum to maximum).

4 Discussion

The increasing incidence of radiation-associated secondary cancers is challenging the treatment strategies for human solid cancers. Based on the tumorigenicity [11], we speculated that the mechanisms responsible for radiation-associated secondary cancers involve the dysregulation of a cluster of genetic factors. As expected, we identified that the upregulation of three collagen genes (COL1A1, COL3A1, and COL1A2), BTG2, and JUNB might be responsible for the radiation-associated secondary cancers in patients with BCa.

COL1A1 and COL3A1, respectively, encodes the α1 chain of Type I and III collagen, both of which are the fibril-forming collagens [14,15]. Type I and Type III procollagens are crucial components of ECM, which is important for tumor microenvironment [14]. They act important roles in the proliferation and/or metastasis of cancer cells. Previous study showed that the Type I and Type III procollagens were elevated in human scirrhous carcinoma of breast with a spatial specificity [16]. In situ hybridization showed that the expression levels of the Type I and Type III procollagens were decreased with the increased distance between the fibroblasts and tumor cells [16]. The upregulation and association of COL1A1, COL3A1, and COL1A2 with collagen prolyl-4-hydroxylase α subunit 2 (P4HA2) had been reported in BCa [17,18,19]. In addition, the other factors that related to ECM or collagens, including MMP2, CCL2, and tissue inhibitor of metalloproteinase-1 (TIMP1), were also identified to be upregulated in BCa tissues compared with control [18]. Here, in our present study, we identified that the exposure to radiotherapy elevated the expression of COL1A1, COL3A1, and COL1A2 in BCa tissues rather than decreased them. According to the above studies, we assumed that the consistent upregulation of the three genes might of great value for exploring the development of radiation-associated secondary nonbreast diseases in BCa.

There are tremendous evidence showing that COL1A1, COL3A1, COL1A2, or P4HA2 promotes the metastasis of BCa and contributes to a poor survival in patients with ER+ BCa [14,18]. By contrast, the inhibition of COL1A1 or P4HA2 counteracted the metastasis and suppressed the proliferation of the BCa cells [14,18]. The study by Srour et al. [20] showed that MMP2, COL1A1, COL3A1, and COL1A2 had lower expression levels in lymph node metastasis compared with triple-negative BCa (TNBC). This finding was in line with the fact that from Gan. [16] who showed that the expression of the Type I and Type III procollagens were decreased with the increased distance between fibroblasts and tumor cells. The interesting evidence was that the elevated COL1A1 expression in BCa had been reported to be correlated with a better response to cisplatin-based chemotherapy [14]. A recent study by Liu et al. [21] showed that there was an opposite conclusion that COL1A1 expression was negatively correlated with radiosensitivity in cervical cancer. Liu et al. [21] reported that the COL1A1 activation could inhibit X-ray radiation-induced apoptosis in cervical cancer. Our present study showed that COL1A1 and COL3A1 were targeted by hsa-miR-29a/b/c that were decreased in radio-resistant nasopharyngeal carcinoma cells [22]. The expression of COL1A1 exerted a radio-resistance effect in nasopharyngeal carcinoma cells [22]. Accordingly, we suspected that the consistent radiation-associated upregulation of the COL1A1, COL3A1, and COL1A2 genes in BCa tissues might be used as genetic susceptibility and risk factors for radio-resistance. This might be related to the radiation-associated secondary nonbreast diseases in patients with BCa.

The association of hsa-miR-29 family members with tumorigenesis and drug-resistance in BCa cells had been proven previously [23,24,25]. hsa-miR-29a acts an oncogenic role [23,24,26], whereas the hsa-miR-29c exhibits a tumor suppressor role in BCa [25,26]. However, we found that the low expression levels of hsa-miR-29a/c were associated with a good survival outcome of BCa. Also, both of them targeted to the upregulated COL1A1 and COL3A1 genes. These results suggested that the predicted miRNA–mRNA regulatory networks, including hsa-miR-29a/c–COL1A1/COL3A1, might have crucial roles in the progression of BCa and the development of radiation-associated secondary diseases.

5 Conclusion

In summary, this present study showed that radiotherapy significantly upregulated the expression of COL1A1, COL3A1, and COL1A2 genes in BCa tumor tissues. The upregulation of them might be risk factors for radiation-associated secondary nonbreast diseases in patients with BCa. However, the association of COL1A1, COL3A1, and COL1A2 upregulation with radiation-associated secondary diseases should be validated using large cohort trials.

Abbreviations

BCa

breast cancer

BRCA

breast invasive carcinoma

CTD

comparative Toxicogenomics Database

DEGs

differentially expressed genes

ECM

extracellular matrix

GEO

gene expression omnibus

IGF1

insulin like growth factor 1

KEGG

Kyoto Encyclopedia of Genes and Genomes

MMP2

matrix metallopeptidase 2

OS

overall survival

PPI

protein–protein interaction

TIMP1

tissue inhibitor of metalloproteinase-1

TNBC

triple-negative breast cancer

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  1. Funding information: This study is supported by Zhejiang Provincial Natural Science Foundation & Zhejiang Society for Mathematical Medicine (LSY19H160002).

  2. Author contributions: Yao GR: conception, study design, data acquisition, analysis and important interpretation, manuscript drafting, and approval of final manuscript; Zhao KY: study design, data acquisition, and analysis; Bao KK: data acquisition and analysis; Bu LY: conception, data analysis and interpretation, manuscript revision, and approval of final manuscript; and Li J: manuscript revision and data acquisition.

  3. Conflict of interest: The authors declare that they have no competing interests.

  4. Data availability statement: The microarray dataset is available at the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/; accession number GSE65505.

Appendix

Table A1

The list of the radiation-associated genes in breast cancer (BCa) in the GSE65505 dataset

Gene symbol
EGR1 HSPA1A COL1A2 FCER1G
ZFP36 S100A10 SNORD99 C1R
FOS HIF1A SNORD114-3 COL1A1
MDM2 PTP4A1 CD68 SGK1
FOSB MMP2 COL14A1 CTSC
CCL2 SOCS3 LGMN PSAP
MT1A PDK4 JUN VWF
LYZ RGS2 COL3A1 XPC
ANXA1 MT1M ABI3BP IGF1
RASD1 NAMPT THBS2 FCGR2C
TNFAIP3 ADAMTS9 MAP4K4 TMEM30A
MT2A GEM NR4A1 ATF3
CCN1 HLA-DRA LRP1 SAMHD1
SERPINE1 SNORD92 EMP3 FPR1
MT1X MT1JP IL6-AS1 TYROBP
KLF6 LAPTM5 MMP19 C5AR1
SLC2A3 MCL1 SERPINF1 CPXM1
SRGN PLTP CTSL FGF7
KRT5 ANXA2 ZMAT3 H19
DUSP1 FAT1 DAB2 SLIT3
NFKBIA NFIL3 IFI30 VGLL3
GPR183 CD163 XGY2 SNORD114-21
EMP1 VIM KLF2 THY1
THBS1 TRIM22 PTCSC1 EDA2R
CCDC80 EFEMP1 GDF15 PLIN2
YBX3 CD248 SPRY1 METRNL
STOM FTL FAM20A VSIG4
SNORD114-14 CDKN1A ADAMTS1 DRAM1
IFI16 SNORD114-12 ECSCR CTSB
RPS19 DNAJB1 C3 STAB1
SAT1 RGS1 IGFBP4 CCL18
BTG2 SNORD114-1 FPR3 *POTEKP
NEAT1 JUNB LAMC1 *ERBB3
DDB2 MRC1 TIMP1 *CYP4X1

*The three downregulated radiation-sensitive genes.

Table A2

The top 15 gene ontology biological processes and the KEGG pathways related to the upregulated radiation-associated genes in breast cancer (BCa)

ID Description Count P value P adjusted Gene symbol
GO:0030198 Extracellular matrix organization 18 1.18 × 10−10 2.15 × 10−7 SERPINE1, THBS1, MMP2, COL1A2, TIMP1, COL1A1, et al.
GO:0043062 Extracellular structure organization 19 1.42 × 10−10 2.15 × 10−7 SERPINE1, THBS1, MMP2, COL1A2, TIMP1, COL1A1, et al.
GO:0071674 Mononuclear cell migration 9 1.46 × 10−8 1.48 × 10−5 SERPINE1, DUSP1, THBS1, RPS19, C5AR1, CCL18, et al.
GO:0050727 Regulation of inflammatory response 17 5.81 × 10−8 4.41 × 10−5 SERPINE1, NEAT1, SOCS3, SERPINF1, IGF1, CCL18, et al.
GO:0070997 Neuron death 14 1.77 × 10−7 7.54 × 10−5 EGR1, FOS, CCL2, BTG2, LRP1, SERPINF1, ERBB3, et al.
GO:0002683 Negative regulation of immune system process 16 1.78 × 10−7 7.54 × 10−5 ZFP36, THBS1, COL3A1, FCER1G, THY1, VSIG4, et al.
GO:0071276 Cellular response to cadmium ion 6 2.16 × 10−7 7.54 × 10−5 FOS, MT1A, MT2A, MT1X, MT1M, JUN
GO:0031589 Cell-substrate adhesion 14 2.18 × 10−7 7.54 × 10−5 SERPINE1, THBS1, COL3A1, MAP4K4, COL1A1, et al.
GO:0030099 Myeloid cell differentiation 15 2.58 × 10−7 7.54 × 10−5 ZFP36, THBS1, HIF1A, JUNB, KLF2, FCER1G, et al.
GO:0010038 Response to metal ion 14 3.06 × 10−7 7.54 × 10−5 FOSB, THBS1, HIF1A, JUNB, JUN, SERPINF1, et al.
hsa04933 AGE-RAGE signaling pathway in diabetic complications 8 1.03 × 10−5 9.25 × 10−4 EGR1, CCL2, SERPINE1, MMP2, COL1A2, JUN, et al.
hsa04115 p53 signaling pathway 7 1.05 × 10−5 9.25 × 10−4 MDM2, SERPINE1, THBS1, DDB2, IGF1, et al.
hsa04151 PI3K-Akt signaling pathway 14 2.02 × 10−5 1.18 × 10−3 THBS1, COL1A2, THBS2, COL1A1, IGF1, ERBB3, et al.
hsa05205 Proteoglycans in cancer 10 6.11 × 10−5 2.03 × 10−3 THBS1, MMP2, COL1A1, IGF1, ERBB3, et al.
hsa04380 Osteoclast differentiation 8 6.22 × 10−5 2.03 × 10−3 FOS, FOSB, JUNB, JUN, FCGR2C, TYROBP, et al.
hsa05150 Staphylococcus aureus infection 7 6.92 × 10−5 2.03 × 10−3 FPR3, C1R, FCGR2C, FPR1, C5AR1, et al.
hsa05140 Leishmaniasis 6 1.62 × 10−4 3.58 × 10−3 FOS, NFKBIA, HLA-DRA, JUN, C3, FCGR2C
hsa04612 Antigen processing and presentation 6 1.74 × 10−4 3.58 × 10−3 HSPA1A, HLA-DRA, LGMN, CTSL, IFI30, CTSB
hsa04668 TNF signaling pathway 7 1.83 × 10−4 3.58 × 10−3 FOS, CCL2, SOCS3, JUNB, JUN, et al.
hsa04145 Phagosome 8 2.07 × 10−4 3.64 × 10−3 THBS1, THBS2, CTSL, C3, C1R, FCGR2C, et al.

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Received: 2021-01-09
Revised: 2022-01-18
Accepted: 2022-01-19
Published Online: 2022-02-17

© 2022 Guorong Yao et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/med-2022-0436
Keywords for this article
radiotherapy; secondary cancer; breast cancer; Type I collagen; Type III collagen
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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