The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

Abstract

The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells

“…Earlier clinicopathological analyses demonstrated that higher expression of PRMT5 was correlated with advanced tumor grade, presence of lymph node metastasis and poor prognosis (19,34,35). Consistent with previous studies by Zhang et al (17,18) and Shimizu et al (19), PRMT5 was significantly overexpressed in our HCC patient tissue samples, confirming the validity of these findings. Notably, our clinicopathological findings indicated the association among higher expression of PRMT5 with more frequent presence of microscopic hepatic invasion and higher AFP levels.…”

“…Extensive analysis of PRMT5 in relation to human cancer has revealed its significant overexpression in various types of cancer, including breast (27) and gastric cancer (28), lymphoma (5,7,29) leukemia (7,30) and prostate cancer (31)(32)(33). Earlier clinicopathological analyses demonstrated that higher expression of PRMT5 was correlated with advanced tumor grade, presence of lymph node metastasis and poor prognosis (19,34,35). Consistent with previous studies by Zhang et al (17,18) and Shimizu et al (19), PRMT5 was significantly overexpressed in our HCC patient tissue samples, confirming the validity of these findings.…”

“…To our knowledge, this is the first study to report such a correlation and our results further highlight the importance of PRMT5 as a potential HCC biomarker. In addition to in vivo studies, several in vitro experiments have revealed that depletion of PRMT5 induced a decrease in cancer cell survival (36) and proliferation (19,28,34,(36)(37)(38). While these phenotypes have been observed in various cancer cell lines, the exact molecular mechanisms remain to be established.…”

“…However, the expression of PRMT5 in relation to invasion phenotypes in HCC and colon cancer has rarely been documented. Earlier invasion studies using siRNAs were conducted under conditions of decreased proliferation and increased cell death, which potentially contributed to the decrease in the invasion activity of cancer cells (17)(18)(19)(20). Using HCC microarray datasets, we have evaluated several molecular markers differentially expressed in HCC (21)(22)(23).…”

“…The PRMT5-mediated decrease in invasion may be attributable to alterations in proliferation and apoptosis. In fact, the PRMT family has been shown to be involved in protein arginine methylation during cell death and proliferation (17)(18)(19)(20). Accordingly, we performed colony survival analysis with a view to observe phenotypic changes, including cellular proliferation and death.…”