Home Bioinformatic analysis reveals GSG2 as a potential target for breast cancer therapy
Article Open Access

Bioinformatic analysis reveals GSG2 as a potential target for breast cancer therapy

  • Zheng Ye , Zhaoyu Zhang , Lijiao Fang , Daiquan Tian and Xin Liu EMAIL logo
Published/Copyright: December 31, 2019
Download Article (PDF)
Open Life Sciences
From the journal Open Life Sciences Volume 14 Issue 1

Abstract

Objective

To explore the potential role of GSG2 in breast cancer progression.

Methods

The mRNA expression, DNA copy number and clinical data used in this study were obtained from the TCGA data portal. The copy number variations (CNVs) thresholds were determined according to the set of discrete copy number calls provided by Genomic Identification of Significant Targets in Cancer (GISTIC).

Results

The mRNA expression level of GSG2 in 112 breast cancer tissues was much higher than that in adjacent normal tissues. GSG2 was significantly upregulated in stage II compared with stage I, and there was no differential expression of GSG2 between tumors with or without metastasis. Heterozygous deletion occupied 57.1% of CNVs for GSG2 gene in breast cancer samples. Patients with higher GSG2 expression tended to suffer from poorer prognosis.

Conclusion

Our profiling analysis indicated the overexpression of GSG2 might play an important role in breast cancer development, suggesting that GSG2 could be a new target for breast cancer treatment, making GSG2 inhibitors becoming potential drugs for breast cancer therapy.

Keywords: GSG2; Breast cancer; CNV

1 Introduction

According to the Global Cancer statistics, there were an estimated 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 [1]. Breast cancer is the second commonly diagnosed cancer and the second leading cause of cancer death [1], which makes it essential to study the mechanism of breast cancer progression and to find new targets for breast cancer treatment.

The mRNA of Haspin was first discovered in male germ cells of mice, therefore, the gene and protein were given the names GSG2 (germ cell-specific gene 2) and HASPIN (haploid cell-specific protein kinase), respectively [2]. Haspin localizes in nucleus in interphase cells [2, 3], and is predominantly associated with chromosomes, especially centrosomes in mitosis [4, 5]. Despite the absence of some of the highly conserved motifs found in canonical eukaryotic protein kinases, mammalian HASPIN proteins have been proved definitively to have serine/threonine kinase activity, and its only substrate is histone H3 [4, 6, 7]. Haspin phosphorylates histone H3 during mitosis and plays an important role in regulating chromosome behavior during cell division [8]. Haspin depletion results in a defect in chromosome congression and a delay in exit from mitosis [9, 10].

In our study, we found that the transcription of GSG2 gene is upregulated in breast cancer tissues and its expression changes across different PAM50 subtype breast cancer samples. GSG2 mRNA expression is significantly upregulated in stage II breast cancer compared with stage I. Furthermore, CNV analysis indicated that CNV is not the main reason for the upregulation of GSG2 in breast cancer. Finally, we showed that patients with higher GSG2 mRNA expression tend to suffer from poorer prognoses. Our study makes GSG2 gene a potential new target for breast cancer treatment.

2 Methods

2.1 Data source and curation

The mRNA expression, DNA copy number and clinical data used in this research were obtained from TCGA data portal (http://portal.gdc.cancer.gov/). The 112 paired breast cancer and adjacent tissue samples were used to analyze the GSG2 gene differential expression. P value was determined by paired t-test.

A total of 1080 tumor samples were used to analyze the mRNA levels of GSG2 among four stages and four PAM50 subtypes according to clinical data. P values between any two groups in stage analysis or PAM50 subtype analysis were determined by Mann-Whitney U test.

To test the robustness, 60% of the original samples were randomly picked up to test the expression difference and repeated 100 times. Sample function in the R package “base” was used to randomly selected samples. R package “sampling” was used to selected samples by stratified sampling.

To validate the results of the TCGA data, the mRNA expression data; CNV data; and clinical information of METABRIC dataset (http://www.cbioportal.org/datasets) which contains 1904 tumor samples were also downloaded and analyzed.

2.2 CNV and expression relationship

To determine the copy number status of GSG2, Genomic Identification of Significant Targets in Cancer (GISTIC) algorithms (http://software.broadinstitute.org/cancer/cga/gistic) was used to analyze the segmentation files downloaded from TCGA. The CNV thresholds were determined according to the set of discrete copy number calls provided by GISTIC: homozygous deletion (-2), heterozygous deletion (-1), diploid (0), gain (1) and amplification (2). The Mann-Whitney U test was used to determine whether the mRNA levels differences were significant between any two CNV statuses.

2.3 Survival analysis

To perform Kaplan-Meier survival analysis, R package “survival” was used to analyze TCGA BRCA clinical data and expression data in tumor samples. The low expression was defined by expression levels lower than the median (n = 539) and high expression was defined by expression levels higher than the median (n = 540). The log-rank test was used to compare the difference of survival curves. P value < 0.05 was considered statistically significant.

All analyses were performed using R 3.5.1.

3 Results

3.1 The mRNA expression levels of GSG2 are higher in breast cancer tissues compared to their normal counterparts

It has been reported that many mitotic players are often upregulated in tumor samples due to an elevated mitotic index in tumor cells [11, 12]. Our previous works focused on proteins or factors involved in mitosis and their roles in tumorigenesis and tumor development. To examine the differential expression genes in breast cancer, we downloaded the TCGA BRCA data set, and calculated the expression difference of 17805 genes between 112 tumor-normal paired samples. The results showed that there are 877 genes upregulated in breast cancer samples (P value < 0.001) (Figure 1a). GSG2 protein is essential for proper chromosome congression during mitosis. To investigate the potential function of GSG2 in breast cancer, we focused on its mRNA expression level in breast cancer tissues. The analysis revealed that the mRNA expression level of GSG2 in breast cancer tissues is much higher than that in adjacent normal tissues (Figure 1b).

Figure 1 The mRNA expression levels of GSG2 are higher in breast cancer tissues compared to normal counterparts. a. Expression levels of 17805 genes in breast cancer and adjacent tissue pairs (n = 112) were analyzed and expression heat map was shown. Statistical analysis was performed using paired t-test (p < 0.001). b. Data for the GSG2 mRNA expression levels in breast cancer tumor and normal tissue pairs were calculated. Box plots showed the differential expression of GSG2 between breast cancer (n = 112) and normal (n = 112) samples. Statistical analysis was performed using paired t-test (p < 0.001). c. The mRNA expression levels of GSG2 were all higher in tumor tissues than normal tissues according to PAM50 intrinsic subtyping. Box plots showed the differential expression of GSG2 between cancer and normal samples in luminal A (n = 35 pairs), luminal B (n = 14 pairs), HER2-enriched (n = 5 pairs) and basal-like (n = 11 pairs) subtypes, respectively. Statistical analysis were performed using paired t-test (p < 0.001 in luminal A, luminal B and basal-like tumor samples, p = 0.012 in HER2-enriched tumor samples).
Figure 1

The mRNA expression levels of GSG2 are higher in breast cancer tissues compared to normal counterparts. a. Expression levels of 17805 genes in breast cancer and adjacent tissue pairs (n = 112) were analyzed and expression heat map was shown. Statistical analysis was performed using paired t-test (p < 0.001). b. Data for the GSG2 mRNA expression levels in breast cancer tumor and normal tissue pairs were calculated. Box plots showed the differential expression of GSG2 between breast cancer (n = 112) and normal (n = 112) samples. Statistical analysis was performed using paired t-test (p < 0.001). c. The mRNA expression levels of GSG2 were all higher in tumor tissues than normal tissues according to PAM50 intrinsic subtyping. Box plots showed the differential expression of GSG2 between cancer and normal samples in luminal A (n = 35 pairs), luminal B (n = 14 pairs), HER2-enriched (n = 5 pairs) and basal-like (n = 11 pairs) subtypes, respectively. Statistical analysis were performed using paired t-test (p < 0.001 in luminal A, luminal B and basal-like tumor samples, p = 0.012 in HER2-enriched tumor samples).

To test the robustness, 60% of the original samples were randomly picked up to test the expression difference and repeated 100 times. The results confirmed the differential expression of GSG2 between breast cancer tissues and adjacent tissues (Fig. S1).

Figure 2 The expression levels of GSG2 changes across different PAM50 subtype breast cancer samples. Box plots showed the differential expression of GSG2 in luminal A (n = 226), luminal B (n = 125), HER2-enriched (n = 57) and Basal-like (n = 97) tumor samples. P values were determined by Mann-Whitney U test.
Figure 2

The expression levels of GSG2 changes across different PAM50 subtype breast cancer samples. Box plots showed the differential expression of GSG2 in luminal A (n = 226), luminal B (n = 125), HER2-enriched (n = 57) and Basal-like (n = 97) tumor samples. P values were determined by Mann-Whitney U test.

Figure 3 The expression level of GSG2 is higher in stage II tumor samples and is not associated with metastasis. a. Box plots showed the differential expression of GSG2 across tumor samples in stage I (n = 178), stage II (n = 611), stage III (n = 247) and stage IV (n = 20). b. Box plots showed the expression of GSG2 in metastatic tumor samples (M1, n = 22) and non-metastatic tumor samples (M0, n = 894). Statistical analysis was performed using the Mann-Whitney U test.
Figure 3

The expression level of GSG2 is higher in stage II tumor samples and is not associated with metastasis. a. Box plots showed the differential expression of GSG2 across tumor samples in stage I (n = 178), stage II (n = 611), stage III (n = 247) and stage IV (n = 20). b. Box plots showed the expression of GSG2 in metastatic tumor samples (M1, n = 22) and non-metastatic tumor samples (M0, n = 894). Statistical analysis was performed using the Mann-Whitney U test.

Figure 4 GSG2 genomic copy number variations (CNVs) mainly centered on heterozygous deletion. a. Data for the GSG2 CNVs were downloaded from the TCGA dataset and analyzed by GISTIC. Bar plot showed the distribution of GSG2 CNVs across tumor samples and heatmaps showed percentage of GSG2 CNVs in different stages. The percentages were calculated by row. b. Different CNVs statuses of GSG2 were plotted against the corresponding mRNA expressions of the gene (Homozygous Deletion: n = 6, Heterozygous Deletion: n = 620, Diploid: n = 383, Gain: n = 68, and Amplification: n = 3). Statistical analysis was performed using the Mann-Whitney U test.
Figure 4

GSG2 genomic copy number variations (CNVs) mainly centered on heterozygous deletion. a. Data for the GSG2 CNVs were downloaded from the TCGA dataset and analyzed by GISTIC. Bar plot showed the distribution of GSG2 CNVs across tumor samples and heatmaps showed percentage of GSG2 CNVs in different stages. The percentages were calculated by row. b. Different CNVs statuses of GSG2 were plotted against the corresponding mRNA expressions of the gene (Homozygous Deletion: n = 6, Heterozygous Deletion: n = 620, Diploid: n = 383, Gain: n = 68, and Amplification: n = 3). Statistical analysis was performed using the Mann-Whitney U test.

Figure 5 Kaplan-Meier plot of overall survival associated with the mRNA expression level of GSG2 in TCGA BRCA. The x axis was the overall survival (OS) month, and the y axis represented the survival rate. Statistical analysis was performed using log-rank test.
Figure 5

Kaplan-Meier plot of overall survival associated with the mRNA expression level of GSG2 in TCGA BRCA. The x axis was the overall survival (OS) month, and the y axis represented the survival rate. Statistical analysis was performed using log-rank test.

Figure S1 Sixty percent of the original samples were randomly picked up to test the expression difference and repeated 100 times. Bar plots showed the –log (P values) of 100 time statistical analysis. P values were determined by paired t-test. The value of –log (0.001) appear as red line.
Figure S1

Sixty percent of the original samples were randomly picked up to test the expression difference and repeated 100 times. Bar plots showed the –log (P values) of 100 time statistical analysis. P values were determined by paired t-test. The value of –log (0.001) appear as red line.

According to breast cancer PAM50 intrinsic subtyping criteria, we divided these breast cancer samples into four types (luminal A, luminal B, Her2-enriched, and basal-like breast cancer), and analyzed the mRNA expression of GSG2 in tumor and adjacent normal tissues. The results showed that the mRNA levels of GSG2 in these four subtypes of breast cancer samples are all significantly higher than that in the corresponding adjacent samples (Figure 1c and Fig. S2).

Figure S2 Sixty percent of the original samples were randomly picked up to test the expression difference and repeated. Bar plots showed the –log (P values) of 100 times statistical analysis for luminal A, luminal B, and basal-like subtypes and the –log (P values) of 10 times statistical analysis for HER2-enriched. P values were determined by paired t-test. The value of –log (0.05) appear as red line.
Figure S2

Sixty percent of the original samples were randomly picked up to test the expression difference and repeated. Bar plots showed the –log (P values) of 100 times statistical analysis for luminal A, luminal B, and basal-like subtypes and the –log (P values) of 10 times statistical analysis for HER2-enriched. P values were determined by paired t-test. The value of –log (0.05) appear as red line.

3.2 The expression levels of GSG2 changes across different PAM50 subtype breast cancer samples

Furthermore, we analyzed the expression levels of GSG2 in different PAM50 subtype breast cancers. It turns out that GSG2 expression in luminal A breast cancers is the lowest and its expression in basal-like breast cancer is the highest in these four subtypes of breast cancer samples (Figure 2 and Fig. S3). Analysis using METABRIC dataset showed consistent results with TCGA dataset (Fig. S5).

Figure S3 Differential expression of GSG2 from 60% of original PAM50 subtype cancer samples. Bar plots showed the –log (P values) of 100 times statistical analysis for any two PAM50 subtype groups. P values were determined by paired t-test. The value of –log (0.01) appear as red line.
Figure S3

Differential expression of GSG2 from 60% of original PAM50 subtype cancer samples. Bar plots showed the –log (P values) of 100 times statistical analysis for any two PAM50 subtype groups. P values were determined by paired t-test. The value of –log (0.01) appear as red line.

Figure S4 Differential expression of GSG2 from 60% of metastatic and non-metastatic samples. Bar plots showed the –log (P values) of 100 times statistical analysis. P values were determined by t-test. The value of –log (0.05) appear as red line.
Figure S4

Differential expression of GSG2 from 60% of metastatic and non-metastatic samples. Bar plots showed the –log (P values) of 100 times statistical analysis. P values were determined by t-test. The value of –log (0.05) appear as red line.

Figure S5 The expression levels of GSG2 changes across different PAM50 subtype breast cancer samples. Box plots showed the differential expression of GSG2 in luminal A (n = 679), luminal B (n = 461), HER2-enriched (n = 220) and Basal-like (n = 199) tumor samples. P values were determined by Mann-Whitney U test.
Figure S5

The expression levels of GSG2 changes across different PAM50 subtype breast cancer samples. Box plots showed the differential expression of GSG2 in luminal A (n = 679), luminal B (n = 461), HER2-enriched (n = 220) and Basal-like (n = 199) tumor samples. P values were determined by Mann-Whitney U test.

3.3 The expression level of GSG2 is higher in stage II tumor samples and is not associated with metastasis

To further study the probable role of GSG2 in the progression of breast cancer, we analyzed the difference of GSG2 expression in 1,056 breast cancer samples classified according to tumor stages, and found that GSG2 is significantly up-regulated in stage II compared with stage I (Figure 3a), suggesting that the increase of GSG2 expression may play an important role in the development from stage I breast cancer to stage II. Moreover, there was no difference in the expression of GSG2 between tumors with or without metastasis (Figure 3b and Fig. S4), indicating that GSG2 may not be involved in breast cancer metastasis. Results from the METABRIC dataset are consistent with that from the TCGA dataset as well (Fig. S6).

Figure S6 The expression level of GSG2 is higher in early tumor samples. Box plots showed the differential expression of GSG2 across tumor samples in stage 0 (n = 11), stage 1 (n = 500), stage 2 (n = 829), stage 3 (n = 118) and stage 4 (n = 10).
Figure S6

The expression level of GSG2 is higher in early tumor samples. Box plots showed the differential expression of GSG2 across tumor samples in stage 0 (n = 11), stage 1 (n = 500), stage 2 (n = 829), stage 3 (n = 118) and stage 4 (n = 10).

3.4 CNVs are not the main reason for the upregulation of GSG2 in breast cancers

DNA copy number variations (CNVs) can result in the upregulation of oncogenes and downregulation of tumor suppressors in human cancers [13], and CNV-derived gene dysregulation is common in various cancers [14, 15]. Therefore, we hypothesized that the overexpression of GSG2 might originate from increased copy number of this gene. To test this, we calculated the copy number variation distribution of the GSG2 gene in 1,080 breast cancer samples. The results showed that there are 593 breast cancer samples (57.1%) containing heterozygous deletion of the GSG2 gene, however, there is a very low frequency of GSG2 gene amplification (< 1%) and GSG2 gene gain (< 7%) in breast cancer samples (Figure 4a). We also analyzed the variation of the copy number of the gene in relation to the clinical stage and found that the three tumor samples with GSG2 gene amplification were all in stage II, and GSG2 gene gain happened most frequently in stage II among the four stages (Figure 4a).

We continue to explore the relationship between copy number variability and expression level of GSG2. The analysis showed that GSG2 expression in tumors with the GSG2 gene gain and GSG2 gene amplification is evidently higher than diploid (Figure 4b and Fig. S7). However, the GSG2 expression in tumor samples with homozygous deletion of the gene (the most common pattern of GSG2 genomic copy number variations in breast cancer tissues) is not significantly lower than that in tumor tissues with diploid (Figure 4b and Fig. S7). These results indicated that CNVs are not the main reason for the upregulation of GSG2 in breast cancers, suggesting that there are important transcription factors and epigenetic factors upregulating GSG2.

Figure S7 GSG2 genomic copy number variations (CNVs) mainly centered on heterozygous deletion. Different CNVs statuses of GSG2 were plotted against the corresponding mRNA expressions of the gene (Homozygous Deletion: n = 5, Heterozygous Deletion: n = 929, Diploid: n = 934, Gain: n = 30, and Amplification: n = 6). Statistical analysis was performed using the Mann-Whitney U test.
Figure S7

GSG2 genomic copy number variations (CNVs) mainly centered on heterozygous deletion. Different CNVs statuses of GSG2 were plotted against the corresponding mRNA expressions of the gene (Homozygous Deletion: n = 5, Heterozygous Deletion: n = 929, Diploid: n = 934, Gain: n = 30, and Amplification: n = 6). Statistical analysis was performed using the Mann-Whitney U test.

3.5 Higher GSG2 expression is associated with poorer prognosis of breast cancer patients

Furthermore, we employed the TCGA and the METABRIC dataset for survival analysis to reveal the potential prognostic value underlying the GSG2 overexpression in breast cancer tissues. The results indicated that patients with higher GSG2 expression tend to suffer from poorer prognoses (Figure 5 and Fig S8).

Figure S8 Kaplan-Meier plot of overall survival associated with the mRNA expression level of GSG2 in METABRIC dataset. The x axis was the overall survival (OS) month, and the y axis represented the survival rate. Statistical analysis was performed using log-rank test.
Figure S8

Kaplan-Meier plot of overall survival associated with the mRNA expression level of GSG2 in METABRIC dataset. The x axis was the overall survival (OS) month, and the y axis represented the survival rate. Statistical analysis was performed using log-rank test.

4 Discussion

GSG2 has been proved to be a serine/threonine kinase that phosphorylates histone 3 during mitosis and plays an important role in regulating chromosome behavior during cell division [3, 6, 7]. Because of its essential activities in mitosis, GSG2 inhibitors have been developed as potential anti-cancer drugs recently [16, 17, 18, 19]. Lili Han et al found that haspin inhibitor CHR-6494 inhibited the viability of several melanoma cell lines [20]. And Jong-Eun Kim et al investigated a natural compound, coumestrol, which exhibits broad anti-cancer effects against skin melanoma, lung cancer and colon cancer cell growth due to the direct targeting of GSG2 [21].

In our present study, we found that transcription of the GSG2 gene is upregulated in breast cancer tissues, and the differential expression occurs in four PAM50 subtypes breast cancer samples. GSG2 mRNA expression is significantly upregulated in stage II breast cancer compared with stage I, indicating that the increase in GSG2 expression may play an important role in the development of breast cancer. To investigate the reason to give rise to its overexpression, we analyzed DNA copy number variations of the GSG2 gene and found that heterozygous deletion occupies 57.1% of 1,080 breast cancer samples. Further exploration showed that GSG2 expression in tumors with GSG2 gene gain and gene amplification is evidently higher than diploid. However, the GSG2 expression in tumor samples with homozygous deletion of the gene is not significantly lower than that in tumor tissues with diploid. Although CNV-derived gene dysregulation is common in human cancers [14, 15], CNVs are not the main reason for the upregulation of GSG2 in breast cancers based on our analysis, suggesting that there are important transcription factors and epigenetic factors responsible for upregulating GSG2. Finally, TCGA data showed that patients with higher GSG2 mRNA expression tend to suffer from poorer prognosis.

Our findings suggest that GSG2 could be a new target for breast cancer treatment, making GSG2 inhibitors potential drugs for breast cancer therapy.

#The authors contributed equally to this work.

  1. Conflict of interest: Authors state no conflict of interest

References

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.10.3322/caac.21492Search in Google Scholar PubMed

[2] Tanaka H, Yoshimura Y, Nozaki M, Yomogida K, Tsuchida J, Tosaka Y, et al. Identification and characterization of a haploid germ cell-specific nuclear protein kinase (Haspin) in spermatid nuclei and its effects on somatic cells. J Biol Chem. 1999;274(24):17049-57.10.1074/jbc.274.24.17049Search in Google Scholar PubMed

[3] Dai J, Sultan S, Taylor SS, Higgins JM. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 2005;19(4):472-88.10.1101/gad.1267105Search in Google Scholar PubMed PubMed Central

[4] Dai J, Higgins JM. Haspin: a mitotic histone kinase required for metaphase chromosome alignment. Cell Cycle. 2005;4(5):665-8.10.4161/cc.4.5.1683Search in Google Scholar PubMed

[5] Moura DS, Campillo-Marcos I, Vazquez-Cedeira M, Lazo PA. VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis. Cellular and molecular life sciences : CMLS. 2018;75(14):2591-611.10.1007/s00018-018-2746-7Search in Google Scholar PubMed PubMed Central

[6] Tanaka H, Iguchi N, Nakamura Y, Kohroki J, de Carvalho CE, Nishimune Y. Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase. Mol Hum Reprod. 2001;7(3):211-8.10.1093/molehr/7.3.211Search in Google Scholar PubMed

[7] Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, et al. Structure and functional characterization of the atypical human kinase haspin. Proc Natl Acad Sci U S A. 2009;106(48):20198-203.10.1073/pnas.0901989106Search in Google Scholar PubMed PubMed Central

[8] Bastea LI, Hollant LMA, Doppler HR, Reid EM, Storz P. Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death. Scientific reports. 2019;9(1):16588.10.1038/s41598-019-53223-0Search in Google Scholar PubMed PubMed Central

[9] Dai J, Sullivan BA, Higgins JM. Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Dev Cell. 2006;11(5):741-50.10.1016/j.devcel.2006.09.018Search in Google Scholar PubMed

[10] Markaki Y, Christogianni A, Politou AS, Georgatos SD. Phosphorylation of histone H3 at Thr3 is part of a combinatorial pattern that marks and configures mitotic chromatin. J Cell Sci. 2009;122(Pt 16):2809-19.10.1242/jcs.043810Search in Google Scholar PubMed

[11] Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 2012;13(3):189-203.10.1038/nrg3123Search in Google Scholar PubMed

[12] Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, et al. Antitumor activity of a kinesin inhibitor. Cancer Res. 2004;64(9):3276-80.10.1158/0008-5472.CAN-03-3839Search in Google Scholar

[13] Albertson DG. Gene amplification in cancer. Trends Genet. 2006;22(8):447-55.10.1016/j.tig.2006.06.007Search in Google Scholar PubMed

[14] Desai A, Menon SP, Dy GK. Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options. Cancer Biol Med. 2016;13(1):77-86.10.20892/j.issn.2095-3941.2016.0008Search in Google Scholar

[15] Tian HX, Zhang XC, Wang Z, Chen JG, Chen SL, Guo WB, et al. Establishment and application of a multiplex genetic mutation-detection method of lung cancer based on MassARRAY platform. Cancer Biol Med. 2016;13(1):68-76.10.20892/j.issn.2095-3941.2015.0094Search in Google Scholar

[16] Cuny GD, Robin M, Ulyanova NP, Patnaik D, Pique V, Casano G, et al. Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorganic & medicinal chemistry letters. 2010;20(12):3491-4.10.1016/j.bmcl.2010.04.150Search in Google Scholar PubMed PubMed Central

[17] Cuny GD, Ulyanova NP, Patnaik D, Liu JF, Lin X, Auerbach K, et al. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorganic & medicinal chemistry letters. 2012;22(5):2015-9.10.1016/j.bmcl.2012.01.028Search in Google Scholar PubMed PubMed Central

[18] Wang P, Hua X, Bryner YH, Liu S, Gitter CB, Dai J. Haspin inhibition delays cell cycle progression through interphase in cancer cells. Journal of cellular physiology. 2019:1-12.10.1002/jcp.29328Search in Google Scholar PubMed PubMed Central

[19] Tanaka H, Wada M, Park J. HASPIN kinase inhibitor CHR-6494 suppresses intestinal polyp development, cachexia, and hypogonadism in Apcmin/+ mice. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation. 2019.10.1097/CEJ.0000000000000562Search in Google Scholar PubMed PubMed Central

[20] Han L, Wang P, Sun Y, Liu S, Dai J. Anti-Melanoma Activities of Haspin Inhibitor CHR-6494 Deployed as a Single Agent or in a Synergistic Combination with MEK Inhibitor. Journal of Cancer. 2017;8(15):2933-43.10.7150/jca.20319Search in Google Scholar PubMed PubMed Central

[21] Kim J-E, Lee S-Y, Jang M, Choi H-K, Kim JH, Chen H, et al. Coumestrol Epigenetically Suppresses Cancer Cell Proliferation: Coumestrol Is a Natural Haspin Kinase Inhibitor. International Journal of Molecular Sciences. 2017;18(10):2228.10.3390/ijms18102228Search in Google Scholar PubMed PubMed Central

Received: 2019-03-25
Accepted: 2019-10-21
Published Online: 2019-12-31

© 2019 Zheng Ye et al. published by De Gruyter

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

Articles in the same Issue

  1. Plant Sciences
  2. Extended low temperature and cryostorage longevity of Salix seeds with desiccation control
  3. Genome-wide analysis of the WRKY gene family and its response to abiotic stress in buckwheat (Fagopyrum tataricum)
  4. Differential expression of microRNAs during root formation in Taxus chinensis var. mairei cultivars
  5. Metabolomics Approach for The Analysis of Resistance of Four Tomato Genotypes (Solanum lycopersicum L.) to Root-Knot Nematodes (Meloidogyne incognita)
  6. Beneficial Effects of Salt on Halophyte Growth: Morphology, Cells, and Genes
  7. Phosphate-solubilizing bacteria from safflower rhizosphere and their effect on seedling growth
  8. Anatomy and Histochemistry of the Roots and Shoots in the Aquatic Selenium Hyperaccumulator Cardamine hupingshanensis (Brassicaceae)
  9. Effects of LED light on Acacia melanoxylon bud proliferation in vitro and root growth ex vitro
  10. Ecology and Environmental Sciences
  11. Intensity of stripping and sugar content in the bark and the bast of European beech (Fagus sylvatica)
  12. Influence of monometallic and bimetallic phytonanoparticles on physiological status of mezquite
  13. Loci identification of a N-acyl homoserine lactone type quorum sensing system and a new LysR-type transcriptional regulator associated with antimicrobial activity and swarming in Burkholderia gladioli UAPS07070
  14. Bacillus methylotrophicus has potential applications against Monilinia fructicola
  15. Evaluation of Heavy Metals and Microbiological Contamination of Selected herbals from Palestine
  16. The effect of size of black cherry stumps on the composition of fungal communities colonising stumps
  17. Effect of rhamnolipids on microbial biomass content and biochemical parameters in soil contaminated with coal tar creosote
  18. Effects of foliar trichomes on the accumulation of atmospheric particulates in Tillandsia brachycaulos
  19. Isolation and characterisation of the agarolytic bacterium Pseudoalteromonas ruthenica
  20. Comparison of soil bioconditioners and standard fertilization in terms of the impact on yield and vitality of Lolium perenne and soil biological properties
  21. Biomedical Sciences
  22. The number of regulatory B cells is increased in mice with collagen-induced arthritis
  23. Lactate overload inhibits myogenic activity in C2C12 myotubes
  24. Diagnostic performance of serum CK-MB, TNF-α and hs-CRP in children with viral myocarditis
  25. Correlation between PPARGC1A gene rs8192678 G>A polymorphism and susceptibility to type-2 diabetes
  26. Improving the Detection of Hepatocellular Carcinoma using serum AFP expression in combination with GPC3 and micro-RNA miR-122 expression
  27. The ratio of neutrophil to lymphocyte is a predictor in endometrial cancer
  28. Expression of HER2/c-erbB-2, EGFR protein in gastric carcinoma and its clinical significance
  29. Clinical significance of neuropeptide Y expression in pelvic tissue in patients with pelvic floor dysfunction
  30. Overexpression of RASAL1 indicates poor prognosis and promotes invasion of ovarian cancer
  31. The effect of adrenaline on the mineral and trace element status in rats
  32. Effects of Ischemic Post-Conditioning on the Expressions of LC3-II and Beclin-1 in the Hippocampus of Rats after Cerebral Ischemia and Reperfusion
  33. Long non-coding RNA DUXAP8 regulates the cell proliferation and invasion of non-small-cell lung cancer
  34. Risk factors of regional lymph node metastasis in patients with cervical cancer
  35. Bullous prurigo pigmentosa
  36. Association of HIF-1α and NDRG2 expression with EMT in gastric cancer tissues
  37. Decrease in the level of nervonic acid and increased gamma linolenic acid in the plasma of women with polycystic ovary syndrome after a three-month low-glycaemic index and caloric reduction diet
  38. Depletion of VAX2 restrains the malignant progression of papillary thyroid carcinoma by modulating ERK signaling pathway
  39. Insulin resistance is a risk factor for mild cognitive impairment in elderly adults with T2DM
  40. Nurr1 promotes lung cancer apoptosis via enhancing mitochondrial stress and p53-Drp1 pathway
  41. Predictive significance of serum MMP-9 in papillary thyroid carcinoma
  42. Agmatine prevents oxidative-nitrative stress in blood leukocytes under streptozotocin-induced diabetes mellitus
  43. Effect of platelet-rich plasma on implant bone defects in rabbits through the FAK/PI3K/AKT signaling pathway
  44. The diagnostic efficacy of thrombelastography (TEG) in patients with preeclampsia and its association with blood coagulation
  45. Value of NSE and S100 Protein of Kawasaki Disease with aseptic meningitis in Infant
  46. CB2 receptor agonist JWH133 activates AMPK to inhibit growth of C6 glioma cells
  47. The effects of various mouthwashes on osteoblast precursor cells
  48. Co-downregulation of GRP78 and GRP94 induces apoptosis and inhibits migration in prostate cancer cells
  49. SKA3 up-regulation promotes lung adenocarcinoma growth and is a predictor of poor prognosis
  50. Protective effects and mechanisms of microRNA-182 on oxidative stress in RHiN
  51. A case of syphilis with high bone arsenic concentration from early modern cemetery (Wroclaw, Poland)
  52. Study of LBHD1 Expression with Invasion and Migration of Bladder Cancer
  53. 1-Hydroxy-8-methoxy-anthraquinon reverses cisplatin resistance by inhibiting 6PGD in cancer cells
  54. Andrographolide as a therapeutic agent against breast and ovarian cancers
  55. Accumulation of α-2,6-sialyoglycoproteins in the muscle sarcoplasm due to Trichinella sp. invasion
  56. Astragalus polysaccharides protects thapsigargin-induced endoplasmic reticulum stress in HT29 cells
  57. IGF-1 via PI3K/Akt/S6K signaling pathway protects DRG neurons with high glucose-induced toxicity
  58. Intra-arterial tirofiban in a male nonagenarian with acute ischemic stroke: A case report
  59. Effects of Huaiqihuang Granules adjuvant therapy in children with primary nephrotic syndrome
  60. Immune negative regulator TIPE2 inhibits cervical squamous cancer progression through Erk1/2 signaling
  61. Asymptomatic mediastinal extra-adrenal paraganglioma as a cause of sudden death: a case Report
  62. Primary mucinous adenocarcinoma of appendix invading urinary bladder with a fistula: a case report
  63. Minocycline attenuates experimental subarachnoid hemorrhage in rats
  64. Neural Remodeling of the Left Atrium in rats by Rosuvastatin following Acute Myocardial Infarction
  65. Protective effects of emodin on lung injuries in rat models of liver fibrosis
  66. RHOA and mDia1 promotes apoptosis of breast cancer cells via a high dose of doxorubicin treatment
  67. Bacteria co-colonizing with Clostridioides difficile in two asymptomatic patients
  68. A allele of ICAM-1 rs5498 and VCAM-1 rs3181092 is correlated with increased risk for periodontal disease
  69. Treatment of hepatic cystic echinococcosis patients with clear cell renal carcinoma: a case report
  70. Edaravone exerts brain protective function by reducing the expression of AQP4, APP and Aβ proteins
  71. Correlation between neutrophil count and prognosis in STEMI patients with chronic renal dysfunction: a retrospective cohort study
  72. Bioinformatic analysis reveals GSG2 as a potential target for breast cancer therapy
  73. Nuciferine prevents hepatic steatosis by regulating lipid metabolismin diabetic rat model
  74. Analysis of SEC24D gene in breast cancer based on UALCAN database
  75. Bioengineering and Biotechnology
  76. Co-cultured Bone-marrow Derived and Tendon Stem Cells: Novel Seed Cells for Bone Regeneration
  77. Animal Sciences
  78. Comparative analysis of gut microbiota among the male, female and pregnant giant pandas (Ailuropoda Melanoleuca)
  79. Adaptive immunity and skin wound healing in amphibian adults
  80. Hox genes polymorphism depicts developmental disruption of common sole eggs
  81. The prevalence of virulence genes and multidrug resistance in thermophilic Campylobacter spp. isolated from dogs
  82. Agriculture
  83. Effect of Lactobacillus plantarum supplementation on production performance and fecal microbial composition in laying hens
  84. Identification of Leaf Rust Resistance Genes in Selected Wheat Cultivars and Development of Multiplex PCR
  85. Determining Potential Feed Value and Silage Quality of Guar Bean (Cyamopsis tetragonoloba) Silages
  86. Food Science
  87. Effect of Thermal Processing on Antioxidant Activity and Cytotoxicity of Waste Potato Juice
https://doi.org/10.1515/biol-2019-0078
Keywords for this article
GSG2; Breast cancer; CNV
Creative Commons
BY 4.0

Articles in the same Issue

  1. Plant Sciences
  2. Extended low temperature and cryostorage longevity of Salix seeds with desiccation control
  3. Genome-wide analysis of the WRKY gene family and its response to abiotic stress in buckwheat (Fagopyrum tataricum)
  4. Differential expression of microRNAs during root formation in Taxus chinensis var. mairei cultivars
  5. Metabolomics Approach for The Analysis of Resistance of Four Tomato Genotypes (Solanum lycopersicum L.) to Root-Knot Nematodes (Meloidogyne incognita)
  6. Beneficial Effects of Salt on Halophyte Growth: Morphology, Cells, and Genes
  7. Phosphate-solubilizing bacteria from safflower rhizosphere and their effect on seedling growth
  8. Anatomy and Histochemistry of the Roots and Shoots in the Aquatic Selenium Hyperaccumulator Cardamine hupingshanensis (Brassicaceae)
  9. Effects of LED light on Acacia melanoxylon bud proliferation in vitro and root growth ex vitro
  10. Ecology and Environmental Sciences
  11. Intensity of stripping and sugar content in the bark and the bast of European beech (Fagus sylvatica)
  12. Influence of monometallic and bimetallic phytonanoparticles on physiological status of mezquite
  13. Loci identification of a N-acyl homoserine lactone type quorum sensing system and a new LysR-type transcriptional regulator associated with antimicrobial activity and swarming in Burkholderia gladioli UAPS07070
  14. Bacillus methylotrophicus has potential applications against Monilinia fructicola
  15. Evaluation of Heavy Metals and Microbiological Contamination of Selected herbals from Palestine
  16. The effect of size of black cherry stumps on the composition of fungal communities colonising stumps
  17. Effect of rhamnolipids on microbial biomass content and biochemical parameters in soil contaminated with coal tar creosote
  18. Effects of foliar trichomes on the accumulation of atmospheric particulates in Tillandsia brachycaulos
  19. Isolation and characterisation of the agarolytic bacterium Pseudoalteromonas ruthenica
  20. Comparison of soil bioconditioners and standard fertilization in terms of the impact on yield and vitality of Lolium perenne and soil biological properties
  21. Biomedical Sciences
  22. The number of regulatory B cells is increased in mice with collagen-induced arthritis
  23. Lactate overload inhibits myogenic activity in C2C12 myotubes
  24. Diagnostic performance of serum CK-MB, TNF-α and hs-CRP in children with viral myocarditis
  25. Correlation between PPARGC1A gene rs8192678 G>A polymorphism and susceptibility to type-2 diabetes
  26. Improving the Detection of Hepatocellular Carcinoma using serum AFP expression in combination with GPC3 and micro-RNA miR-122 expression
  27. The ratio of neutrophil to lymphocyte is a predictor in endometrial cancer
  28. Expression of HER2/c-erbB-2, EGFR protein in gastric carcinoma and its clinical significance
  29. Clinical significance of neuropeptide Y expression in pelvic tissue in patients with pelvic floor dysfunction
  30. Overexpression of RASAL1 indicates poor prognosis and promotes invasion of ovarian cancer
  31. The effect of adrenaline on the mineral and trace element status in rats
  32. Effects of Ischemic Post-Conditioning on the Expressions of LC3-II and Beclin-1 in the Hippocampus of Rats after Cerebral Ischemia and Reperfusion
  33. Long non-coding RNA DUXAP8 regulates the cell proliferation and invasion of non-small-cell lung cancer
  34. Risk factors of regional lymph node metastasis in patients with cervical cancer
  35. Bullous prurigo pigmentosa
  36. Association of HIF-1α and NDRG2 expression with EMT in gastric cancer tissues
  37. Decrease in the level of nervonic acid and increased gamma linolenic acid in the plasma of women with polycystic ovary syndrome after a three-month low-glycaemic index and caloric reduction diet
  38. Depletion of VAX2 restrains the malignant progression of papillary thyroid carcinoma by modulating ERK signaling pathway
  39. Insulin resistance is a risk factor for mild cognitive impairment in elderly adults with T2DM
  40. Nurr1 promotes lung cancer apoptosis via enhancing mitochondrial stress and p53-Drp1 pathway
  41. Predictive significance of serum MMP-9 in papillary thyroid carcinoma
  42. Agmatine prevents oxidative-nitrative stress in blood leukocytes under streptozotocin-induced diabetes mellitus
  43. Effect of platelet-rich plasma on implant bone defects in rabbits through the FAK/PI3K/AKT signaling pathway
  44. The diagnostic efficacy of thrombelastography (TEG) in patients with preeclampsia and its association with blood coagulation
  45. Value of NSE and S100 Protein of Kawasaki Disease with aseptic meningitis in Infant
  46. CB2 receptor agonist JWH133 activates AMPK to inhibit growth of C6 glioma cells
  47. The effects of various mouthwashes on osteoblast precursor cells
  48. Co-downregulation of GRP78 and GRP94 induces apoptosis and inhibits migration in prostate cancer cells
  49. SKA3 up-regulation promotes lung adenocarcinoma growth and is a predictor of poor prognosis
  50. Protective effects and mechanisms of microRNA-182 on oxidative stress in RHiN
  51. A case of syphilis with high bone arsenic concentration from early modern cemetery (Wroclaw, Poland)
  52. Study of LBHD1 Expression with Invasion and Migration of Bladder Cancer
  53. 1-Hydroxy-8-methoxy-anthraquinon reverses cisplatin resistance by inhibiting 6PGD in cancer cells
  54. Andrographolide as a therapeutic agent against breast and ovarian cancers
  55. Accumulation of α-2,6-sialyoglycoproteins in the muscle sarcoplasm due to Trichinella sp. invasion
  56. Astragalus polysaccharides protects thapsigargin-induced endoplasmic reticulum stress in HT29 cells
  57. IGF-1 via PI3K/Akt/S6K signaling pathway protects DRG neurons with high glucose-induced toxicity
  58. Intra-arterial tirofiban in a male nonagenarian with acute ischemic stroke: A case report
  59. Effects of Huaiqihuang Granules adjuvant therapy in children with primary nephrotic syndrome
  60. Immune negative regulator TIPE2 inhibits cervical squamous cancer progression through Erk1/2 signaling
  61. Asymptomatic mediastinal extra-adrenal paraganglioma as a cause of sudden death: a case Report
  62. Primary mucinous adenocarcinoma of appendix invading urinary bladder with a fistula: a case report
  63. Minocycline attenuates experimental subarachnoid hemorrhage in rats
  64. Neural Remodeling of the Left Atrium in rats by Rosuvastatin following Acute Myocardial Infarction
  65. Protective effects of emodin on lung injuries in rat models of liver fibrosis
  66. RHOA and mDia1 promotes apoptosis of breast cancer cells via a high dose of doxorubicin treatment
  67. Bacteria co-colonizing with Clostridioides difficile in two asymptomatic patients
  68. A allele of ICAM-1 rs5498 and VCAM-1 rs3181092 is correlated with increased risk for periodontal disease
  69. Treatment of hepatic cystic echinococcosis patients with clear cell renal carcinoma: a case report
  70. Edaravone exerts brain protective function by reducing the expression of AQP4, APP and Aβ proteins
  71. Correlation between neutrophil count and prognosis in STEMI patients with chronic renal dysfunction: a retrospective cohort study
  72. Bioinformatic analysis reveals GSG2 as a potential target for breast cancer therapy
  73. Nuciferine prevents hepatic steatosis by regulating lipid metabolismin diabetic rat model
  74. Analysis of SEC24D gene in breast cancer based on UALCAN database
  75. Bioengineering and Biotechnology
  76. Co-cultured Bone-marrow Derived and Tendon Stem Cells: Novel Seed Cells for Bone Regeneration
  77. Animal Sciences
  78. Comparative analysis of gut microbiota among the male, female and pregnant giant pandas (Ailuropoda Melanoleuca)
  79. Adaptive immunity and skin wound healing in amphibian adults
  80. Hox genes polymorphism depicts developmental disruption of common sole eggs
  81. The prevalence of virulence genes and multidrug resistance in thermophilic Campylobacter spp. isolated from dogs
  82. Agriculture
  83. Effect of Lactobacillus plantarum supplementation on production performance and fecal microbial composition in laying hens
  84. Identification of Leaf Rust Resistance Genes in Selected Wheat Cultivars and Development of Multiplex PCR
  85. Determining Potential Feed Value and Silage Quality of Guar Bean (Cyamopsis tetragonoloba) Silages
  86. Food Science
  87. Effect of Thermal Processing on Antioxidant Activity and Cytotoxicity of Waste Potato Juice
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 9.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/biol-2019-0078/html
Scroll to top button