GINS Complex Subunit 4, a Prognostic Biomarker and Reversely Mediated by Krüppel-like Factor 4, Promotes the Growth of Colorectal Cancer

Overview

Journal Cancer Sci

Specialty Oncology

Date 2020 Feb 4

PMID 32012389

Citations 23

Authors

Zeyin Rong

Zai Luo

Jianming Zhang

Tengfei Li

Zhonglin Zhu

Zhilong Yu

Zhongmao Fu

Zhengjun Qiu

Chen Huang

Affiliations

Soon will be listed here.

Abstract

GINS complex subunit 4 (GINS4) is essential for DNA replication initiation and elongation in the G /S phase cell cycle in eukaryotes, however, its functional roles and molecular mechanisms remain unclear in many aspects. Our study was designed to investigate the clinical significance, biological function, and molecular mechanism of GINS4 in colorectal cancer (CRC). First, we confirmed that GINS4 expression was significantly overexpressed in CRC cells and tissues. The immunohistochemical results in tissue microarray from 106 CRC patients showed that a high level of GINS4 expression was positively correlated with advanced T stage, higher tumor TNM stage, and poor differentiation. The results from univariate and multivariate survival analysis models based on 106 CRC patients revealed that GINS4 might serve as an independent prognostic indicator for overall survival and disease-free survival of CRC patients. Moreover, downregulated GINS4 can inhibit growth and the cell cycle and accelerate cell apoptosis progression in vitro as well as inhibit tumorigenesis in vivo. Besides, our results also indicated that Krüppel-like factor 4 (KLF4) can negatively regulate GINS4 expression at the transcriptional level and the KLF/GINS4 pathway might play a vital role in the growth and prognosis of CRC.

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References

Zhu Z, Yu Z, Rong Z, Luo Z, Zhang J, Qiu Z . The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42. Theranostics. 2019; 9(26):8294-8311. PMC: 6857050. DOI: 10.7150/thno.36256. View

Feng J, Yang Y, Zhang P, Wang F, Ma Y, Qin H . miR-150 functions as a tumour suppressor in human colorectal cancer by targeting c-Myb. J Cell Mol Med. 2014; 18(10):2125-34. PMC: 4244026. DOI: 10.1111/jcmm.12398. View

Treinies I, PATERSON H, Hooper S, Wilson R, Marshall C . Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal To stimulate DNA synthesis. Mol Cell Biol. 1998; 19(1):321-9. PMC: 83890. DOI: 10.1128/MCB.19.1.321. View

Lee J, Loh K, Yap Y . PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biol Med. 2016; 12(4):342-54. PMC: 4706528. DOI: 10.7497/j.issn.2095-3941.2015.0089. View

MacNeill S . Structure and function of the GINS complex, a key component of the eukaryotic replisome. Biochem J. 2010; 425(3):489-500. DOI: 10.1042/BJ20091531. View

Gong Z, Kidoya H, Mohri T, Han Y, Takakura N . DNA damage enhanced by the attenuation of SLD5 delays cell cycle restoration in normal cells but not in cancer cells. PLoS One. 2014; 9(10):e110483. PMC: 4204874. DOI: 10.1371/journal.pone.0110483. View

Zhang J, Zhu Z, Wu H, Yu Z, Rong Z, Luo Z . PODXL, negatively regulated by KLF4, promotes the EMT and metastasis and serves as a novel prognostic indicator of gastric cancer. Gastric Cancer. 2018; 22(1):48-59. PMC: 6314994. DOI: 10.1007/s10120-018-0833-y. View

Gouge C, Christensen T . Drosophila Sld5 is essential for normal cell cycle progression and maintenance of genomic integrity. Biochem Biophys Res Commun. 2010; 400(1):145-50. PMC: 2939264. DOI: 10.1016/j.bbrc.2010.08.033. View

Kidger A, Sipthorp J, Cook S . ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway. Pharmacol Ther. 2018; 187:45-60. DOI: 10.1016/j.pharmthera.2018.02.007. View

10.

Chen W, Zheng R, Baade P, Zhang S, Zeng H, Bray F . Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2):115-32. DOI: 10.3322/caac.21338. View

11.

Chen D, Li Y, Zhang X, Wu H, Wang Q, Cai J . Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation. Oncogene. 2019; 38(37):6429-6444. PMC: 6756236. DOI: 10.1038/s41388-019-0891-6. View

12.

Eberspaecher H, Seldin M, de Crombrugghe B . A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem. 1996; 271(49):31384-90. DOI: 10.1074/jbc.271.49.31384. View

13.

Yamane K, Naito H, Wakabayashi T, Yoshida H, Muramatsu F, Iba T . Regulation of SLD5 gene expression by miR-370 during acute growth of cancer cells. Sci Rep. 2016; 6:30941. PMC: 4976388. DOI: 10.1038/srep30941. View

14.

Guan Q, Zeng Q, Yan H, Xie J, Cheng J, Ao L . A qualitative transcriptional signature for the early diagnosis of colorectal cancer. Cancer Sci. 2019; 110(10):3225-3234. PMC: 6778657. DOI: 10.1111/cas.14137. View

15.

Ma Y, Wu L, Liu X, Xu Y, Shi W, Liang Y . KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling. Oncol Rep. 2017; 38(2):975-984. DOI: 10.3892/or.2017.5736. View

16.

Zhu Z, Rong Z, Luo Z, Yu Z, Zhang J, Qiu Z . Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis. Mol Cancer. 2019; 18(1):126. PMC: 6704702. DOI: 10.1186/s12943-019-1054-7. View

17.

Patel N, Ghaleb A, Nandan M, Yang V . Expression of the tumor suppressor Krüppel-like factor 4 as a prognostic predictor for colon cancer. Cancer Epidemiol Biomarkers Prev. 2010; 19(10):2631-8. PMC: 2952064. DOI: 10.1158/1055-9965.EPI-10-0677. View

18.

Qu X, Yan X, Kong C, Zhu Y, Li H, Pan D . c-Myb promotes growth and metastasis of colorectal cancer through c-fos-induced epithelial-mesenchymal transition. Cancer Sci. 2019; 110(10):3183-3196. PMC: 6778643. DOI: 10.1111/cas.14141. View

19.

Bermudez V, Farina A, Raghavan V, Tappin I, Hurwitz J . Studies on human DNA polymerase epsilon and GINS complex and their role in DNA replication. J Biol Chem. 2011; 286(33):28963-28977. PMC: 3190704. DOI: 10.1074/jbc.M111.256289. View

20.

Shields J, Yang V . Identification of the DNA sequence that interacts with the gut-enriched Krüppel-like factor. Nucleic Acids Res. 1998; 26(3):796-802. PMC: 147321. DOI: 10.1093/nar/26.3.796. View