The Expression and Function Mechanisms of RAP1 in Hepatocellular Carcinoma

YANG Yue¹^#, ZHANG Kun²^#, GAO Jing³, SHEN Lijun¹, FANG Hezhi¹, DONG Jieying¹*

(¹Key Laboratory of Laboratory Medicine Designated by the Chinese Ministry of Education, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China;²Department of Clinical Laboratory, Xi’an Daxing Hospital, Xi’an 710016, China;³General Office of Beijing Haidian Health School, Beijing 100192, China)

Abstract:

RAP1 (RAS-associated protein 1) is one of small GTPases belonging to RAS family, which has long been associated with the development of varies of cancers. However, the causal role of RAP1 in HCC (hepatocellular carcinoma) and its mechanism were not known. The conjoint analysis of TCGA and GTEx showed that the mRNA levels of RAP1A and RAP1B in HCC tissues were significantly higher than those in normal liver tissues. Both immunohistochemistry and WB (Western blot) analysis confirmed that the RAP1 level in tumor tissues was higher than that in paired adjacent normal tissues from HCC patients. In vitro study showed that, RAP1 depletion in HCC cells resulted in delayed cell proliferation, decreased cell migration and invasion when compared with control cells. Mechanistically, RAP1 depletion boosts mitochondrial oxidative phosphorylation, inhibits glycolysis, and activates p38 MAPK pathway. Whereas p38 MAPK inhibition suppresses HCC mitochondrial function. These findings suggest that RAP1 can promote HCC progression by converting the cell metabolism from oxidative phosphorylation
to glycolysis via inhibition of p38 MAPK pathway. Although further studies are required to clarify how RAP1 regulates p38 MAPK pathway and its downstream energy metabolic reprogramming, these findings provide a new therapeutic target for the treatment of HCC.

CSTR: 32200.14.cjcb.2021.10.0001