TPI1‐reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis

Abstract

Rab GTPases are major mediators that ensure the proper spatiotemporal regulation of intracellular trafficking. Functional impairment and altered expression of Rab proteins have been revealed in various human cancers. There is an emerging evidence about the role of Rab proteins in the biogenesis of extracellular vesicles (EVs). In hepatocellular carcinoma (HCC), using RNA sequencing comparing expression profiles of adjacent non‐tumorous tissues and HCC, Rab20 is identified to be the most frequently downregulated Rab member in HCC. Functionally, restoration of Rab20 in metastatic HCC cells results in the release of EVs with a diminished activity to promote cell growth, motility and metastasis. Conversely, EVs released from normal liver cells with Rab20 knockdown loses suppressive effect on HCC cell growth and motility. Proteomic profiling revealed the level of triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, in EVs to be positively associated with Rab20 expression of the releasing cells. TPI1 targeted to be expressed in EVs released by Rab20 knockdown cells compromises the oncogenic activity of EVs. Besides, EVs released by TPI1 knockdown cells recapitulates the promoting effect of EVs derived from HCC cells with Rab20 underexpression. Aerobic glycolysis is beneficial to the survival and proliferation of tumour cells. Here, we observed that the enhanced cell growth and motility are driven by the enhanced aerobic glycolysis induced by EVs with reduced TPI1. The addition of glycolytic inhibitor blocks the promoting effect of EVs with reduced TPI1. Taken together, our study provides a mechanistic link among tumour cell‐derived EVs and glucose metabolism in HCC with Rab20 deregulation.

RAB20 Promotes Proliferation via G2/M Phase through the Chk1/cdc25c/cdc2-cyclinB1 Pathway in Penile Squamous Cell Carcinoma

“…Recent studies have revealed that RAB20, which plays a role in the control of endocytotic vesicle transport, is involved in the progression of multiple cancers [ 15 , 16 , 17 , 36 ]. Amillet et al [ 15 ] first identified that the overexpression of RAB20 in pancreatic intraductal neoplasia lesions is an early event in the course of pancreatic cancer progression [ 15 ].…”

“…A recent study on neuronal network formation showed that RAB20, as a novel regulator, participated in neurite outgrowth and cell proliferation [ 37 ]. Liu et al [ 36 ] found that the restoration of RAB20 expression in hepatocellular carcinoma cells inhibited cell growth, motility, and metastasis. To further investigate the oncogenic functions of RAB20 in regulating the malignant phenotype, validation and rescue experiments were conducted in vitro and in vivo.…”

Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer

“…Previous studies have demonstrated that TPI1 and RAN exerted crucial effects on tumor initiation and progression [ 37 – 40 ]. For example, the reduction of TPI1 in extracellular vesicles mediated by Rab20 downregulation facilitates aerobic glycolysis to drive hepatocarcinogenesis [ 41 ]. RAN promotes membrane targeting and stabilization of RhoA to enhance ovarian cancer cell growth and invasiveness [ 42 ].…”

Network preservation analysis reveals dysregulated metabolic pathways in human vascular smooth muscle cell phenotypic switching

“…RAB20 expression was downregulated in proliferative SMCs (P-value <0.001). Downregulation of RAB20 has been shown to promote glycolysis and contribute to enhanced cell proliferation and motility 48 . KD analysis identified a novel KD gene in the proliferative BN, MPI.…”