RMP Promotes Human Liver Cancer Proliferation By Maintaining Mitochondrial Homeostasis

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is thesixth most common cancer worldwide and is ranked third in mortality amongcancer-related diseases. It has high incidence in our country. Initiation and development ofHCC is a complex process, which is affected by many factors, including gene mutations,environment stresses and drug toxicity. It has been reported that the onset of cancer washighly related to mitochondria. There is little evidence about changes in mitochondrialmass in primary tumor, but increasing evidence shows that key oncogenes and tumorsuppressors modulate mitochondrial dynamics through important signaling pathways.Mitochondrial mass and function vary between tumors and individuals but the significanceof these events for cancer are not fully appreciated. Mitochondrial mass in cells isregulated by both changes in mitochondrial biogenesis and mitophagy, two processes thatare tightly regulated in response to cellular stress, including nutrient availability, oxidativedamage, and redox state. Mitochondrial biogenesis and mitophagy are both influenced bythe activity of key oncogenes and tumor suppressors. Macro-autophagy is a catabolicprocess that plays a housekeeping role in eliminating protein aggregates andmalfunctioning organelles, such as mitochondria, and is also activated in response tonutrient deprivation to provide energy. And mitochondrial autophagy has its special form.Based on what is known about regulation of mitochondrial mass in tumor cell lines, onemight expect that changes in cancers might be linked to specific oncogenic lesions, whichreflect the heterogeneity of tumor, Our data identifies significant variation inmitochondrial mass between tumors in different individuals. Finding the role ofmitochondria in hepatocellular carcinoma (HCC) may help the classification of livercancer therapy.URI, or RMP, is a RNA polymerase II subunit RPB5-associated protein known to beessential for ubiquitination and transcription. Previous studies have reported that theRMP/URI participate in the mTOR signaling pathway, which suggested that RMP mayplay a role in the development of cancer. Recent studies show that the RMP/URI issignificant for the process of liver, ovarian and prostate cancer. Lack of RMP causes DNA damage, leading to abnormal cell division and proliferation. These studies show that theRMP is an important regulating factor in gene transcription, apoptosis, maintaininggenomic stability and may play an important role in the development of tumor.In this article, we found that RMP promotes liver cancer proliferation bymaintaining mitochondrial homeostasis in HCC, and we found the RMP is highlyexpressed in MHCCLM3、MHCCLM6、MHCC97-L. Then we knocked down RMP inHuh7and HCCLM3. Proliferation tests show that knock-down of RMP in Huh7andHCCLM3inhibits the proliferation. We explored the quantity and function of mitochondriain knocked-down cell and its control cells. The quantity of mitochondria in knocked-downcells is reduced,in comparison with control cells, and more damaged mitochondriapresented in knocked-down cells compared to that in control cells. High level of ROSexpression in knockdown cells suggests that autophagy may be induced in these cells.Western Blot test confirmed that the expression of Parkin and PINK1, which could berecruited to mitochondria when mitophagy occurs, suggests that this kind of autophagymay be mitophagy.Our study show that RMP may affect the proliferation of HCC through regulatingmitophagy. This finding suggests that RMP might potentially be a specific target for thetreatment of HCC.