Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis

Abstract

Polarity defects are frequently involved in liver diseases, such as chronic hepatitis and hepatocellular carcinoma (HCC). It was reported that vacuolar protein sorting 33B (Vps33b) plays critical roles in the maintenance of hepatocyte polarity; however, the functional roles and mechanisms of Vps33b in HCC occurrence and progression remain unknown. First of all, we showed that Vps33b is down-regulated in human and mouse liver cancer samples, and the low expression levels of Vps33b correlate with the poor prognosis of many HCC patients. Liver-specific Vps33b deficiency induces liver damage, progressive hepatitis, fibrosis, and HCC in male mice, indicating that Vps33b is a crucial contributory factor to hepatocarcinogenesis. Vps33b deficiency-caused liver damage was primarily due to the disorders of structural and functional hepatocyte polarity, which were reflected by the decreased protein levels of E-cadherin because of inaccurate location to lysosomes and polarity defects at both apical and lateral plasma membrane proteins. The results of a mechanism study revealed that Vps33b interacts with VPS33B-interacting protein, which is involved in polarity and apical protein restriction; vesicle-trafficking protein Sec22b; and Flotillin-1 in hepatocytes and is in charge of the normal distribution of polarity-determined proteins. Expression levels of Vps33b negatively correlated with the degree of inflammatory cell infiltration in livers from diethylnitrosamine-induced or transgenic HCC mouse models, and the inflammatory stimuli suppressed the expression of Vps33b in vitro. Conclusion: Down-regulation of Vps33b expression is a critical step for inflammation-driven HCC, and Vps33b serves as an important tumor suppressor in hepatocarcinogenesis.

Novel missense mutation in VPS33B is associated with isolated low gamma‐glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome

“…Physically, VPS33B colocalizes and interacts with VIPAR to form the VPS33B/VIPAR complex, interacting with endosome marker RAB11A and playing a vital role in the intracellular trafficking and the hepatocyte polarity maintenance (Golachowska, Hoekstra, & van IJzendoorn, ; Wakabayashi, Dutt, Lippincott‐Schwartz, & Arias, ; C. Wang et al, ). For VPS33B/VIPAR complex defect, aberrant location of canalicular membrane proteins of BSEP, MDR3, and CEA were observed in VPS33B / VIPAR deficient patients and Vps33b knockout mice (Ackermann et al, ; Bull et al, ; Hanley et al, ).…”

CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease

“…High levels of Vps3 correlate with poor prognosis of human squamous carcinoma lung cancer (Bao et al, 2016). Single nucleotide polymorphisms in Vps41 strongly associate with hereditary melanoma (Ibarrola-Villava et al, 2015), and a recent study reported Vps33B as an important tumor suppressor in hepatocarcinogenesis (Wang et al, 2018). In D. melanogaster, mutations in Vps8 and Vps18 lead to the development of melanotic tumors, that is strongly pigmented tumors originating from immune cells (Lorincz et al, 2016).…”

AFP promotes HCC progression by suppressing the HuR-mediated Fas/FADD apoptotic pathway

“…Although an increasing number of diagnostic and therapeutic strategies have been developed, the prognosis of HCC patients remains poor 3 . This is mainly due to the key genes and molecular mechanisms involved in HCC pathogenesis and development remaining largely unclear 3,4 .…”