Abstract

G2 and S phase-expressed-1 (GTSE1) regulates G1/S cell cycle transition. It was recently reported to be overexpressed in certain human cancers, but its significance and mechanism(s) in hepatocellular carcinoma (HCC) remain unknown. Here, we showed preferential GTSE1 upregulation in human HCC tissues and cell lines that positively correlated with Ki67. GTSE1 knockdown by short hairpin RNA resulted in deficient colony-forming ability and depleted capabilities of HCC cells to migrate and invade. Conversely, exogenous GTSE1 overexpression enhanced colony formation and stimulated HCC cell migration and invasion. Furthermore, GTSE1 silencing was associated with the downregulation of N-cadherin, β-catenin, and Snail, whereas GTSE1 overexpression caused the opposite effects. GTSE1 upregulated Snail via both transcription and protein degradation pathways. Additionally, GTSE1 modulated the sensitivity of HCC to 5-fluorouracil therapy. High GTSE1 correlates with chemo-resistance, while low GTSE1 increases drug sensitivity. Kaplan-Meier survival analysis indicated that high GTSE1 levels were significantly associated with poor overall survival. In conclusion, high expression of GTSE1 is commonly noted in HCC and is closely correlated with migration and invasion by epithelial-to-mesenchymal transition (EMT) modulation. Activated GTSE1 significantly interferes with chemotherapy efficacy and influences the probability of survival of patients with HCC. GTSE1 may thus represent a promising molecular target.

Highlights

  • Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, leading to the deaths of approximately 700,000 people per year[1]

  • The GTSE1 protein was predominantly expressed in the nuclei and plasma of the hepatocellular carcinoma (HCC) tumour regions (T), whereas GTSE1 was only occasionally expressed in the liver cells of the adjacent non-cancerous tissues (N)

  • Compared with the immortalized human liver cell line LO2, the QGY7703, BEL-7404, Hepa3B, MHCC-97L, HepaG2.2.15, and SK-HEP-1 cell lines showed elevated protein expression levels of GTSE1 (Fig. 1e). These results demonstrated that GTSE1 expression was increased in HCC tumour tissues and implied that the upregulation of GTSE1 in HCC might play a considerable role in tumour development

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Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, leading to the deaths of approximately 700,000 people per year[1]. A better understanding of the molecular mechanisms underlying liver carcinogenesis and further studies of HCC oncogenes may lead to advances in the identification of novel molecular markers of HCC progression and the development of new diagnostic and therapeutic strategies. Deregulation of cell cycle regulators is one of the major factors contributing to HCC development and tumour progression[3]. Numerous studies indicate that abolishing G1 arrest and/or stimulating G1/S phase transition in the cell cycle facilitate the unrestrained growth of unstable cells, precancerous cells, or cancer cells and are associated with hepatocarcinogenesis and HCC progression[4, 5]. Its function in HCC progression and the underlying molecular mechanisms remain obscure. We evaluated the role of GTSE1 as a prognostic marker and a therapeutic molecular target in HCC

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