Effect of <italic>Mst1</italic> overexpression on the growth of human hepatocellular carcinoma HepG2 cells and the sensitivity to cisplatin <italic>in vitro</italic>

Abstract

Mammalian STE20-like kinase 1 (Mst1) is the mammalian homologue of Drosophila Hippo, a major inhibitor of cell proliferation in Drosophila. It ubiquitously encodes serine threonine kinase that belongs to the family of protein kinases related to yeast STE20, and is involved in cell proliferation, apoptosis, oncogenesis, and organ growth. Recent studies have shown that Mst1 has tumor-suppressor function, and the deletion or mutation of Mst1 is reported to be associated with tumorigenesis. To investigate the effect of overexpression of Mst1 on the growth of human liver cancer cell line HepG2 cells and the sensitivity to cisplatin in vitro, here we constructed recombinant eukaryotic expression vector pEGFP-N1-Mst1 containing Mst1 gene, and transiently transfected into HepG2 cells. The effects of Mst1 overexpression on the cell proliferation and apoptosis, the phosphorylation status of Yes-associated protein, and the mRNA transcript levels of connective tissue growth factor (CTGF), amphiregulin (AREG), and birc5 (Survivin) were determined. Results showed that overexpression of Mst1 inhibited cell proliferation, induced apoptosis of HepG2 cells, promoted YAP (Ser127) phosphorylation, and downregulated the mRNA expression of CTGF, AREG, and Survivin. We also investigated the relationship between the expression and cleavage of Mst1 and cisplatin-induced cell death. We found that Mst1 overexpression could induce cisplatin chemosensitivity, and cisplatin could promote the cleavage of Mst1 without affecting the expression of Mst1. Overall, our results indicated that Mst1 might be a promising anticancer target.

Inhibitory effect and mechanism of exogenous mammalian sterile 20-like kinase 1 on the growth of human colorectal cancer

“…MST1 gene abnormalities are commonly observed in colorectal (13,14), hepatocellular (11,15) and gastric (16) cancer. It has also been found that the expression of YAP in the Hippo pathway is elevated in human primary colorectal cancer (17).…”

“…Zhou et al (10) found that mice lacking MST1/2 could not inhibit the proliferative and anti-apoptotic activity of the carcinogenic gene YAP1, resulting in the formation of liver cell carcinoma. However, subsequent to the transfection of MST1 into HepG2 cells, MST1 was re-expressed, resulting in the loss of the proliferative activity of YAP1, the promotion of apoptosis and the elimination of tumorigenicity (11). …”

Expression and Clinical Significance of YAP, TAZ, and AREG in Hepatocellular Carcinoma

“…These results and our results suggest that YAP plays an important role in human HCC. Moreover, the idea that the overexpression of YAP leads to HCC development was confirmed by experiments in YAP transgenic mice [17]. …”

Ovarian Germline Stem Cells (OGSCs) and the Hippo Signaling Pathway Association with Physiological and Pathological Ovarian Aging in Mice

“…MST1 overexpression not only decreases cell proliferation but also induces apoptosis of the human breast cancer cell line MCF-7. Moreover, the overexpression of MST1 can inhibit cell proliferation and promote the cytoplasmic localization and phosphorylation of YAP (Ser127) protein, which may be one of the tumor inhibitory mechanisms of the MST1 gene [30,31]. Consistent with the major roles of MST in cell proliferation and apoptosis, LATS regulates the balance between proliferation and differentiation during adipose development.…”