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. 2018 Jun 12;9(13):2349-2356.
doi: 10.7150/jca.25098. eCollection 2018.

Synaptotagmin7 Is Overexpressed In Colorectal Cancer And Regulates Colorectal Cancer Cell Proliferation

Kewei Wang  1 , Huimin Xiao  2 , Jiaqi Zhang  1 , Dehua Zhu  1
Affiliations

Synaptotagmin7 Is Overexpressed In Colorectal Cancer And Regulates Colorectal Cancer Cell Proliferation

Kewei Wang et al. J Cancer. .

Abstract

Purpose: Synaptotagmin7 (SYT7) belongs to the synaptotagmin gene family and plays an important role in synaptic transmission. However, the function of this gene in most human cancer especially in colorectal cancer (CRC) remains unknown. In this research, we examined SYT7's role in CRC and tried to reveal its underlying mechanism. Methods: We examined SYT7's expression levels in normal colorectal tissue and CRC tissues from 83 patients and analyzed the possible correlation between the expression level of SYT7 and pathological characteristics. The influences of SYT7 knockdown on cell growth were detected by Celigo image cytometer, colony formation assay, cell cycle analysis and apoptosis assay in vitro. The possible molecular mechanism was assessed using a microarray and Ingenuity Pathway Analysis. Results: Our results show that the expression of SYT7 is upregulated in colorectal cancer tissues in comparison with normal tissues and positively correlated with the pathological stage of colorectal cancer. (P=0.015). We examined SYT7's role in human colorectal cancer cell line RKO by using SYT7-shRNA and revealed that SYT7 knockdown inhibit cell proliferation (P=8.6E-5), clonogenic ability (P=4.5E-6) and promoted G2/M Phase arrest and apoptosis (P=4.6E-7). Multiple cancer-associated pathways regulated by SYT7 were unraveled by microarray and Ingenuity Pathway Analysis. Conclusions: Our study suggests that SYT7 plays an important role in the development of CRC and SYT7 may become a new therapeutic target in CRC.

Keywords: Synaptotagmin7; TCGA; apoptosis; colorectal cancer; proliferation.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
SYT7 is highly expressed in colorectal cancer tissues. (A) After analysis of 50 paired tissues in TCGA database, SYT7 was found to be highly expressed in tumors. (B) SYT7 is over-expressed in 78% (39 of 50) of the colorectal cancer tissues, with an average over-expression of 3.01-fold (P<0.001) as compared to paired normal tissues.
Figure 2
Figure 2
SYT7 expression in colorectal cancer of different stages. SYT7 expression was detected by immunohistochemical staining(IHC) A,C,E,G: normal tissues; B,D,F,H: tumor tissues from stage I to stage IV (magnification, ×200); I: SYT7 expression in colorectal cancer, (magnification, ×400)
Figure 3
Figure 3
Knockdown of SYT7 inhabited RKO cells proliferation and colony formation in vitro. (A) SYT7 expression change at protein level was analyzed by western blot in RKO cells treated as described after 4 days. GAPDH was used as an internal. (B) SYT7 expression change at mRNA level was detected by real-time quantitative PCR. SYT7 mRNA level was normalized to GAPDH. Data shown are the mean±S.D. of three independent experiments. **: P<0.01. (C) Impaired cell proliferation after SYT7 knockdown in RKO cells were detected by Celigo image cytometer. **: P<0.01. (D) Clonogenic ability was impaired in RKO cells by SYT7 knockdown using colony formation assay. The results represent mean±S.D. of three separate experiments. **: P<0.01.
Figure 4
Figure 4
Cell cycle arrest and apoptosis were induced in RKO cells by SYT7 knockdown. (A) The changes in the cell cycles of RKO cells by SYT7 knockdown, the percentage of cells in the S phase significantly increased. Graph shows the mean±S.D. of cell proportion in the G1 phase, S phase and G2/M phase from three separate experiments. **: P<0.01 in S phase and G2/M phase. (B) The changes in the apoptosis rates of RKO cells by SYT7 knockdown. Data shown here is the mean±S.D. of cell percentage in apoptosis from three separate experiments. **: P<0.01.
Figure 5
Figure 5
Widespread changes of gene expressions in RKO cells with SYT7 knockdown. (A) Representation of 1915 genes showed significant differential expressions in RKO cells infected with lentivirus expressing either Scr-shRNA or SYT7-shRNA. A color scale for the normalized expression data was shown at the upper left corner of the microarray heatmap (green represents downregulated genes while red represents upregulated genes). (B) The signal pathway histogram shows the enrichment of the differential gene in the classical signaling pathway based on IPA pathway. All signal paths were sorted using -Log (P-value). Here, the 14 significant-enriched pathways based on a P<0.05 were shown. Z-score> 2 represents that the Pathway is significantly activated, while Z-score <-2 represents that the Pathway is significantly inhibited. Ratio represents the ratio of differentially expressed genes numbers to all gene numbers in this signal pathway. Networks were constructed between SYT7 and genes involved in ATM signaling (C) and mitotic roles of polo-like kinase (D), respectively. Green color represents downregulated genes and red color represents unregulated genes. Solid arrow in the figure means confirmed regulatory relationships and dotted line means predicted regulatory relationships. Inhibitory relationship was represented by "T" bar.
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