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Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation

  • Ling Dang and Yingdong Wang EMAIL logo
Published/Copyright: February 14, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

Background

Previous studies indicated that dysregulated expression of nicotinamide N-methyltransferase (NNMT) contributed to the tumor progression and predicted poor prognosis in various cancers. However, there was no exact conclusion on account of the contradictory results across studies.

Methods

The relevant studies up to December 7, 2020 were searched in PubMed, Web of Science, and Embase. The association between NNMT expression and prognostic outcomes was explored, including overall survival (OS), disease-free survival (DFS), and clinicopathological features. The bioinformatics database was used to validate the findings.

Results

Thirteen retrospective studies containing 2,591 patients with cancers were included in this analysis. High NNMT expression was significantly associated with shorter OS (hazard ratio [HR] = 2.01, 95% confidence interval [CI] = 1.42–2.86, and P < 0.01) and DFS (HR = 1.59, 95% CI = 1.23–2.05, and P < 0.01) compared to low NNMT expression in cancers. Compared to patients with low NNMT expression, patients with high NNMT expression tended to have worse tumor differentiation (P = 0.03), earlier lymph node metastasis (P = 0.01), earlier distant metastasis (P = 0.02), and more advanced clinical stage (P < 0.01).

Conclusion

High NNMT expression is an unfavorable factor of various cancers. NNMT is a promising indicator to predict the prognosis of various cancers and can serve as a potential therapeutic target in various cancers.

Keywords: nicotinamide N-methyltransferase; cancer; prognosis; meta-analysis; TCGA

1 Introduction

Cancer has become one of the major public health concerns globally and the leading cause of death [1]. It is estimated that there were 1,688,780 new cases of cancer and approximately 600,920 deaths resulting from cancer in 2017 in the United States [2]. Despite the great improvement in diagnosis and treatment, many patients suffered from a poor prognosis, especially those at advanced clinical stage [1]. To solve this dilemma, increasing number of researchers are devoted to establishing new potential biomarkers to improve the clinical decision-making and prolong the survival time of cancer patients [3,4].

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the pyridine compounds and N-methylation of nicotinamide [5]. Recently, accumulating evidence showed that abnormal expression of NNMT might play an important role in the tumorigenesis, invasion, and metastasis [6,7,8]. Previous studies have showed that NNMT expression had the potential capacity to predict the prognosis of several cancers, such as endometrial cancer [9], pancreatic cancer [10], and gastric cancer [11]. However, definite conclusion about the prognostic value of NNMT expression in human cancers has not been determined on account of contradictory results among existing evidence [9,10,11,12,13,14,15,16,17,18,19,20,21]. A study by Akar et al. showed that the overexpression of NNMT was associated with the aberrant p53 expression, pAkt, and poor survival (P = 0.03) [9]. Similarly, Chen et al. also found that overexpression of NNMT might predict the shorter survival time (P = 0.03) and be associated with worse clinicopathological features (e.g., distant metastasis and clinical stage) in gastric cancer [11]. However, a different voice from the study of Bi et al. showed that there was no significant relationship between NNMT expression and survival time in pancreatic cancer [10]. Therefore, there is a dispute on the prognostic value of NNMT expression in cancers based on existing evidence [9,10,11,12,13,14,15,16,17,18,19,20,21]. To settle this dispute, we performed this meta-analysis by integrating the existing evidence and validated our findings using the bioinformatics database.

2 Materials and methods

Ethical approval and informed consent were unnecessary because no data of individuals were used in this research.

2.1 Literature search

This study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses [22]. PubMed, Web of Science, and Embase were comprehensively researched for relevant studies on December 26, 2020. The following search strategy was used: (“nicotinamide N-methyltransferase” OR “NNMT”) AND (“cancer” OR “tumor” OR “carcinoma” OR “neoplasm”) AND (“survival” OR “prognosis” OR “predict”). Potential related studies were also searched in the references of the retrieved articles.

2.2 Study inclusion and exclusion criteria

Inclusion criteria for selecting the studies were as follows: (1) patients were diagnosed with any type of cancer; (2) studies explored the association of NNMT expression with clinicopathological parameters (CP) and survival outcomes of cancer patients, such as overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and recurrence-free survival (RFS); (3) studies had the retrospective or prospective design; and (4) studies were published in English. Exclusion criteria were as follows: (1) reviews, case reports, or cell studies; (2) studies without sufficient data; (3) duplication or studies containing duplicated patients; and (4) data of patients were from common bioinformatics database. The study selection was performed by the abovementioned criteria by two authors independently, and disagreement were solved by discussion.

2.3 Data extraction and quality assessment

We extracted the following information of each study using a prepared template: (1) information of the first author, publication year, country, total number of patients, number of patients with high or low NNMT expression, definition of high NNMT expression, detection methods, source of sample, outcomes, analysis model of OS, and adjusted factors in the multivariate analysis; (2) CP including age, gender, tumor size, tumor differentiation, T stage, lymph node metastasis, distant metastasis, and clinical stage; and (3) survival outcomes including OS, CSS, DFS, and RFS. For survival outcomes, hazard ratio (HR) and 95% confidence interval (CI) were directly or indirectly extracted from included studies as previously described [23]. Especially, if HR and 95% CI were both provided by univariate analysis and multivariate analysis, the latter one with higher accuracy would be used. We used the Newcastle-Ottawa scale (NOS), which consisted of 9 scores, to evaluate the quality assessment [24]. Studies with NOS score of >5 were considered to have a high-quality and low risk of bias.

2.4 Database validation

The Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/index.html), based on the data from The Cancer Genome Atlas (TCGA), was used to explore the association of NNMT expression with OS or DFS of patients with various cancers or gastrointestinal cancer [25].

2.5 Statistical analysis

The Stata 12.0 (StataCorp, College Station, TX, USA) and Review Manager 5.3 (Cochrane Collaboration, London, UK) were used to perform the statistical analysis. Heterogeneity was determined by the Chi square-based Q test and I 2 statistics. Heterogeneity across studies was considered significant when P for heterogeneity is <0.05 or I 2 > 50, as a result, a random-effect model was used. Otherwise, a fixed-effect model was applied. Forest plot based on the Z test was generated to determine the association of NNMT expression with OS, DFS, and CP. HR and 95% CI were integrated to show the association between NNMT expression and OS/DFS. Odds ratio (OR) and 95% CI were used to show the association of NNMT expression with CP based on the Z test. P < 0.05 in the Z test indicated that there was a significant association of NNMT expression with survival or CP of human cancers. In addition, we also performed the subgroup analysis to comprehensively explore the association between NNMT expression and OS. Sensitivity analysis was also performed to evaluate the stability of the results. Publication bias referred to the fact that “statistically significant” positive results were more likely to be published than “statistically insignificant” negative or invalid results, which were generally assessed by Begg’s test and Egger’s test, and P value less than 0.05 for Begg’s test and Egger’s test indicated that there was a significant publication bias included across studies [26].

3 Results

3.1 Literature search and selection

The details of literature search and selection are listed in Figure 1. A total of 224 studies were retrieved from common databases, and 13 studies meeting the criteria were finally included in this meta-analysis [9,10,11,12,13,14,15,16,17,18,19,20,21].

Figure 1 Flowchart of literature search and selection.
Figure 1

Flowchart of literature search and selection.

3.2 Characteristics of included studies

As listed in Table 1, 13 retrospective studies containing 2,591 patients were included in this analysis [9,10,11,12,13,14,15,16,17,18,19,20,21]. Eight studies were conducted in China, two studies were conducted in Japan, one study was conducted in Korea, one study was conducted in America, and one study was conducted in Turkey. The sample size ranged from 22 to 967 among studies. There were 1,455 patients in high NNMT expression group and 1,126 patients in low NNMT expression group. The detection methods included immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and enzyme linked immunosorbent assay. The details of the detection methods are listed in Table S1. The expression level of NNMT was detected from cancer tissues in 12 studies and serum in 1 study. The following types of cancer were investigated in the current study: endometrial cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular carcinoma, oral squamous cell carcinoma, colorectal cancer, non-small cell lung cancer, breast cancer, nasopharyngeal carcinoma, and renal cancer. Regarding prognostic outcomes, OS or CSS was reported in nine studies, DFS or RFS was reported in three studies, and CP was reported in nine studies. The association between NNMT expression and OS was determined using multivariate analysis in five studies and univariate analysis in four studies. The adjusted factors in the multivariate analysis of OS are listed in Table S2. NOS score was larger than five in all included studies, which indicated all studies had a relatively high quality and low risk of bias.

Table 1

Demographic and clinical characteristics of 13 included studies

Study Country Sample size (n) Gender (male/female) (n) NNMT expression Source Cancer type Outcomes Analysis model NOS
High/low (n) High NNMT expression Detection method
Akar et al. [9] Turkey 44 0/44 14/30 Score >80 IHC Cancer tissue Endometrial cancer CSS M 7
Bi et al. [10] America 22 NA 14/8 >Median qRT-PCR Cancer tissue Pancreatic cancer OS U 6
Chen et al. [11] China 617 464/153 341/276 Score >120 IHC Cancer tissue Gastric cancer CP and OS M 8
Cui et al. [12] China 30 17/13 22/8 Score >3 IHC Cancer tissue Esophageal carcinoma CP NA 6
Kim et al. [13] Korea 120 92/28 48/72 Copy number ratio ≥4.40 qRT-PCR Cancer tissue Hepatocellular carcinoma CP, OS, and DFS U 8
Liao et al. [14] China 38 37/1 19/19 2+, 3+, 4+ IHC Cancer tissue Oral squamous cell carcinoma CP NA 6
Song et al. [15] China 967 573/394 641/326 Score >106 IHC Cancer tissue Colorectal cancer CP, CSS, and DFS M 9
Ujiie et al. [16] Japan 109 67/42 27/82 >710 pg/mL ELISA Serum Non-small cell lung cancer OS U 7
Wang et al. [17] China 165 0/165 89/76 Score ≥120 IHC Cancer tissue Breast cancer CP NA 6
Win et al. [18] China 124 95/29 62/62 Score >62 IHC Cancer tissue Nasopharyngeal carcinoma CP, CSS, and RFS M 8
Xu et al. [19] China 178 104/74 99/79 Score >110 IHC Cancer tissue Pancreatic cancer CP and OS M 9
Yao et al. [20] Japan 103 75/28 35/68 >Mean qRT-PCR Cancer tissue Renal cancer CSS U 7
Zhang et al. [21] China 74 48/26 54/20 1+, 2+, 3+ IHC Cancer tissue Renal cancer CP NA 6

NNMT, nicotinamide N-methyltransferase; NOS, Newcastle-Ottawa scale; IHC, immunohistochemistry analysis; qRT-PCR, quantitative real time polymerase chain reaction; ELISA, enzyme linked immunosorbent assay; CSS, cancer-specific survival; OS, overall survival; DFS, disease-free survival; RFS, recurrence-free survival; CP, clinicopathological parameters; M, multivariate; U, univariate; NA, not available.

3.3 Association between NNMT expression and OS

Nine studies reporting the OS or CSS were included in the pooled analysis [9,10,11,13,15,16,18,19,20]. A random-effect model was used for obvious heterogeneity across studies (I 2 = 64% and P < 0.01), and high NNMT expression was significantly associated with shorter OS compared to low NNMT expression in human cancers (HR = 2.01, 95% CI = 1.42–2.86, and P < 0.01) (Figure 2). Studies by Song et al. [15] and Yao et al. [20] were the main source of heterogeneity based on the Galbraith plot (Figure 3). Heterogeneity reduced a lot after the removal of the studies by Song et al. [15] and Yao et al. [20] (I 2 = 35% and P = 0.16), and significant relation between NNMT expression and OS of cancers remained (HR = 1.96, 95% CI = 1.61–2.39, and P < 0.01) (Figure 4). We also conduced the subgroup analysis to further determine the association between NNMT expression and OS in cancers. The association between NNMT expression and OS remained significant in most stratified factors (P < 0.05), especially gastrointestinal cancers (P < 0.01) (Table 2).

Figure 2 Meta-analysis for the association between NNMT expression and OS indicating that high NNMT expression was significantly associated with worse OS compared to low NNMT expression in cancer patients.
Figure 2

Meta-analysis for the association between NNMT expression and OS indicating that high NNMT expression was significantly associated with worse OS compared to low NNMT expression in cancer patients.

Figure 3 Galbraith plot for the association between NNMT expression and OS showing that studies of Song et al. and Yao et al. were the main sources of heterogeneity based on the Galbraith plot.
Figure 3

Galbraith plot for the association between NNMT expression and OS showing that studies of Song et al. and Yao et al. were the main sources of heterogeneity based on the Galbraith plot.

Figure 4 Meta-analysis for the association between NNMT expression and OS after the removal of the studies of Song et al. and Yao et al. also indicating that high NNMT expression was significantly associated with worse OS compared to low NNMT expression in cancer patients.
Figure 4

Meta-analysis for the association between NNMT expression and OS after the removal of the studies of Song et al. and Yao et al. also indicating that high NNMT expression was significantly associated with worse OS compared to low NNMT expression in cancer patients.

Table 2

Subgroup analysis of the association between NNMT expression and OS of cancer patients

Factors Studies (n) HR (95% CI) P I 2 (%) P for heterogeneity Model
Continent
 Asian 7 1.94 (1.33, 2.82) <0.01* 67 <0.01 Random
 Others 2 2.49 (0.66, 9.43) 0.18 71 0.07 Random
Sample size (n)
 <150 6 1.78 (1.09, 2.90) 0.02* 53 0.06 Random
 ≥150 3 2.41 (1.35, 4.27) <0.01* 81 <0.01 Random
Detection method
 IHC 5 2.48 (1.62, 3.80) <0.01* 70 0.01 Random
 qRT-PCR 3 1.23 (0.80, 1.89) 0.35 42 0.18 Fixed
 ELISA 1 2.72 (0.64, 11.56) 0.18 NA NA Fixed
Cancer type
 Gastrointestinal cancer 5 2.11 (1.40, 3.18) <0.01* 65 0.02 Random
 Others 4 1.95 (0.90, 4.25) 0.09 70 0.02 Random
Analysis model
 Univariate 4 1.31 (0.87, 1.98) 0.20 34 0.21 Fixed
 Multivariate 5 2.48 (1.62, 3.80) <0.01* 70 0.01 Random
Survival type
 OS 5 1.88 (1.52, 2 .33) <0.01* 33 0.20 Fixed
 CSS 4 2.37 (1.02, 5.55) 0.04* 81 <0.01 Random

NNMT, nicotinamide N-methyltransferase; HR, hazard ratio; CI, confidence interval; OS, overall survival; CSS, cancer-specific survival; IHC, immunohistochemistry analysis; qRT-PCR, quantitative real time polymerase chain reaction; ELISA, enzyme linked immunosorbent assay; NA, not available; * P value less than 0.05 indicate the significant association between NNMT expression and OS.

3.4 Association between NNMT expression and DFS

Three studies reporting DFS or RFS were pooled to determine the association between NNMT expression and DFS in cancers [13,15,18]. A fixed-effect model was used for no heterogeneity across studies (I 2 = 0% and P = 0.58). Cancer patients with high NNMT expression tended to have a shorter DFS compared to those with low NNMT expression (HR = 1.59, 95% CI = 1.23–2.05, and P < 0.01) (Figure 5).

Figure 5 Meta-analysis for the association between NNMT expression and DFS indicated that high NNMT expression was significantly associated with worse DFS compared to low NNMT expression in cancer patients.
Figure 5

Meta-analysis for the association between NNMT expression and DFS indicated that high NNMT expression was significantly associated with worse DFS compared to low NNMT expression in cancer patients.

3.5 Association between NNMT expression and CP

As listed in Table 3, cancer patients with high NNMT expression tended to have worse tumor differentiation (OR = 1.31, 95% CI = 1.02–1.68, and P = 0.03), earlier lymph node metastasis (OR = 1.93, 95% CI = 1.15–3.23, and P = 0.01), earlier distant metastasis (OR = 3.18, 95% CI = 1.22–8.26, and P = 0.02), and more advanced clinical stage (OR = 1.66, 95% CI = 1.36–2.03, and P < 0.01) compared to those with low NNMT expressions. Otherwise, there was no obvious association of NNMT expression with age (P = 0.85), gender (P = 0.71), tumor size (P = 0.14), or T stage (P = 0.29).

Table 3

Meta-analysis for the association between NNMT expression and CP of cancer patients

Items Studies (n) Patients (n) OR (95% CI) P I 2 (%) P for heterogeneity Model Begg’s test Egger’s test
Age (old/young) 7 1,308 1.05 (0.65, 1.67) 0.85 67 <0.01 Random 1.00 0.81
Gender (male/female) 7 2,110 0.96 (0.80, 1.17) 0.71 15 0.32 Fixed 0.37 0.29
Tumor size (large/small) 2 298 1.99 (0.79, 5.02) 0.14 72 0.06 Random NA NA
Differentiation (poor/moderate or well) 7 1,186 1.31 (1.02, 1.68) 0.03* 0 0.49 Fixed 0.13 0.17
T stage (T3 + T4/T1 + T2) 5 1,158 1.44 (0.73, 2.82) 0.29 74 <0.01 Random 1.00 0.47
Lymph node metastasis (yes/no) 7 2,155 1.93 (1.15, 3.23) 0.01* 76 <0.01 Random 0.37 0.26
Distant metastasis (yes/no) 3 960 3.18 (1.22, 8.26) 0.02* 51 0.13 Random 1.00 0.70
Clinical stage (III + IV/I + II) 5 1,864 1.66 (1.36, 2.03) <0.01* 17 0.30 Fixed 0.81 0.62

NNMT, nicotinamide N-methyltransferase; CP, clinicopathological parameters; OR, odds ratio; CI, confidence interval; NA, not available; *P value less than 0.05 indicate the significant association between NNMT expression and CP.

3.6 Sensitivity analysis

Sensitivity analysis was performed by removing any included study in the meta-analysis using Stata 12.0. As shown in Figure 6a, the significant association between NNMT expression and OS was not altered after the removal of any included study, which meant that none of the included studies had the decisive effect on the results. Similarly, the relationship between NNMT expression and DFS remained significant by excluding any included study, which indicated the association between NNMT expression and DFS was reliable (Figure 6a).

Figure 6 Sensitivity analysis indicated that the meta-analysis results for OS and DFS were reliable: (a) OS and (b) DFS.
Figure 6

Sensitivity analysis indicated that the meta-analysis results for OS and DFS were reliable: (a) OS and (b) DFS.

3.7 Publication bias

There was no obvious publication bias across studies in terms of OS (Figure 7a, Begg’s test, P = 0.75 and Figure 7b, Egger’s test, P = 0.65) and DFS (Figure 7c, Begg’s test, P = 1.00 and Figure 7d, Egger’s test, P = 0.40). Moreover, no obvious publication bias was observed in the analysis of CP (Begg’s test, P > 0.05 and Egger’s test, P > 0.05) (Table 3).

Figure 7 Assessment of publication bias for OS and DFS indicated that there was no obvious publication bias across included studies: (a) Begg’s test for OS; (b) Egger’s test for OS; (c) Begg’s test for DFS; and (d) Egger’s test for DFS.
Figure 7

Assessment of publication bias for OS and DFS indicated that there was no obvious publication bias across included studies: (a) Begg’s test for OS; (b) Egger’s test for OS; (c) Begg’s test for DFS; and (d) Egger’s test for DFS.

3.8 Database validation

The GEPAI based on the data from TCGA showed that high NNMT expression was significantly associated with shorter OS (HR = 1.50, 95% CI = 1.31–1.72, and P < 0.01) (Figure 8a) and DFS compared to low NNMT expression in human cancers (HR = 1.20, 95% CI = 1.12–1.28, and P < 0.01) (Figure 8b). Specially, the significant relationship between NNMT expression and prognosis in gastrointestinal cancers was also validated in terms of OS (HR = 1.40, 95% CI = 1.21–1.63, and P < 0.01) (Figure 8c) and DFS (HR = 1.60, 95% CI = 1.33–1.92, and P < 0.01) (Figure 8d).

Figure 8 Database validation using TCGA data confirmed that high NNMT expression was significantly associated with worse OS and DFS in various cancers and gastrointestinal cancer: (a) OS for various cancers; (b) DFS for various cancers; (c) OS for gastrointestinal cancer; and (d) DFS for gastrointestinal cancer.
Figure 8

Database validation using TCGA data confirmed that high NNMT expression was significantly associated with worse OS and DFS in various cancers and gastrointestinal cancer: (a) OS for various cancers; (b) DFS for various cancers; (c) OS for gastrointestinal cancer; and (d) DFS for gastrointestinal cancer.

4 Discussion

Although recent studies have showed that NNMT expression played an important role in the tumor progression and might induce an unfavorable survival outcome for cancer patients, definite conclusion has not been obtained for small sample size and contradictory results of existing evidence [9,10,11,12,13,14,15,16,17,18,19,20,21]. In current study, we performed this meta-analysis to explore the prognostic value of NNMT expression in human cancers, and our study showed that, compared to low NNMT expression, high NNMT expression was significantly associated with shortened OS, DFS, and worse CP, including worse tumor differentiation, earlier lymph node metastasis, earlier distant metastasis, and more advanced clinical stage. Our results showed that there was no obvious publication bias among included studies, which indicated that our results were convincing. Moreover, we also used the TCGA data to validate our findings, and results also showed that high NNMT expression was an unfavorable factor of OS and DFS in human cancers, especially gastrointestinal cancers. Therefore, our study showed that high NNMT expression might predict the worse prognosis of cancer patients, and NNMT expression had the potential capacity to serve as a prognostic factor in various cancers, especially gastrointestinal cancer. Besides, we have noticed that Li et al. performed a similar meta-analysis focusing on the prognostic role of NNMT expression in human cancers [27]. However, some differences between the current study and the study by Li et al. should be mentioned. First, most included data were extracted from glioblastoma patients in the study by Li et al., but we paid more attention to the prognostic value of NNMT expression in the gastrointestinal cancers. Second, we not only explored the association of NNMT expression with cancer survival, but also several vital clinical features (e.g., clinical stage, lymph node metastasis, etc.), which was not performed in the study by Li et al. Third, we used the GEPIA database with a large population to validate our findings, which was not performed in the study by Li et al. Hence, we believe that our study could provide more comprehensive and reliable evidence on this topic.

There are many publications focusing on the underlying mechanism of the prognostic role of NNMT expression in cancers. Wang et al. indicated that NNMT expression could enhance the chemoresistance by sirtuin 1 protein stabilization in breast cancer [17]. Similarly, You et al. also showed that NNMT could promote the tumor progression by stabilizing sirtuin 1 in prostate cancer [28], and Yu et al. indicated that NNMT could inhibit the autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells [29]. Cui et al. supported the idea that downregulation of NNMT expression could inhibit the migration and epithelial-mesenchymal transition of esophageal cancer trough the Wnt/β-catenin pathway [12]. With respect to gastric cancer, Liang et al. suggested that NNMT could promote the epithelial-mesenchymal transition of cancer cells by activating transforming growth factor-β1 expression [30]. Besides, Bi et al. found that miR-1291-altered PANC-1 cell function could increase the expression level of N-methylnicotinamide level and NNMT expression, and they drew the conclusion that NNMT might be indicative of the extent of pancreatic cancer [10]. A study conducted by Palanichamy et al. showed that NNMT could inhibit the tumor suppressor enzyme PP2A by reorganizing the methylome and concomitantly activate the serine/threonine kinases [31]. Moreover, Zhang et al. found that downregulation of NNMT could induce the apoptosis via the mitochondria-mediated pathway in breast cancer cells [32]. The research of Xie et al. manifested that NNMT could enhance the resistance to 5-fluorouracil through inhibition of the ASK1-p38 MAPK pathway in colorectal cancer cells, and further result in the poor prognosis [33].

Our findings, based on the existing evidence, showed that high NNMT expression was associated with worse prognosis of cancer patients, and our findings were further confirmed by the TCGA data. Therefore, the conclusion of our study was reliable and could provide the valuable evidence on the clinical decision-making. Nevertheless, our study was not without limitations. First, all included studies had a retrospective design, which induced the selection bias of patients and further affected our results. Second, prognostic value of NNMT expression was evaluated in all types of cancer because of limited sample size of one specific cancer, which might limit the promotion of our findings. Third, heterogeneity was obvious in some analyses (e.g., clinical stage and lymph node metastasis), and a random-effect model has to be used, which might reduce the accuracy of our results. Fourth, Cox multivariate analysis to determine the independent prognostic factors for the prognosis of cancers failed to be performed in this meta-analysis, because all data in this meta-analysis were extracted from published studies and the data of individuals were unavailable for us. To eliminate these limitations, future studies that are well-designed with enough follow-up period should be performed to determine the prognostic role of NNMT expression in cancers.

5 Conclusion

High NNMT expression was significantly associated with shorter OS, DFS, and worse clinicopathological features compared to low NNMT expression in various cancers. Therefore, NNMT expression could serve as a promising prognostic factor and potential therapeutic target in various cancers, especially gastrointestinal cancer.

Abbreviations

CI

confidence interval

CP

clinicopathological parameters

CSS

cancer-specific survival

DFS

disease-free survival

GEPIA

gene expression profiling interactive analysis

HR

hazard ratio

NNMT

nicotinamide N-methyltransferase

NOS

Newcastle-Ottawa scale

OR

odds ratio

OS

overall survival

RFS

recurrence-free survival

TCGA

The Cancer Genome Atlas

Acknowledgements

We would like to thank the researchers and study participants for their contributions.

  1. Funding information: No funding was received for this study.

  2. Author contributions: Study concepts and design: Yingdong Wang and Ling Dang; Literature search: Yingdong Wang and Ling Dang; Data extraction: Ling Dang and Yingdong Wang; Manuscript preparation and revision: Ling Dang and Yingdong Wang. All authors have participated sufficiently in the study and approved the final version.

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

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-10-08
Revised: 2021-12-08
Accepted: 2021-12-14
Published Online: 2022-02-14

© 2022 Ling Dang and Yingdong Wang, published by De Gruyter

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

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  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
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https://doi.org/10.1515/med-2022-0413
Keywords for this article
nicotinamide N-methyltransferase; cancer; prognosis; meta-analysis; TCGA
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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