Vps34 Inhibits Hepatocellular Carcinoma Invasion by Regulating Endosome-Lysosome Trafficking via Rab7-RILP and Rab11
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Purpose: The role of vacuolar protein sorting 34 (Vps34), an indispensable protein required for cell vesicular trafficking, in the biological behavior of hepatocellular carcinoma (HCC) has yet to be studied. Materials and methods: In the present study, the expression of Vps34 in HCC and the effect of Vps34 on HCC cell invasion was detected both in vivo and in vitro. Furthermore, by modulating the RILP and Rab11, which regulate juxtanuclear lysosome aggregation and recycling endosome respectively, the underlying mechanism was investigated. Results: Vps34 was significantly decreased in HCC and negatively correlated with the HCC invasiveness both in vivo and in vitro. Moreover, Vps34 could promote lysosomal juxtanuclear accumulation, reduce the invasive ability of HCC cells via the Rab7-RILP pathway. In addition, the deficiency of Vps34 in HCC cells affected the endosome-lysosome system, resulting in enhanced Rab11 mediated endocytic recycling of cell surface receptor and increased invasion of HCC cells. Conclusion: Our study reveals that Vps34 acts as an invasion suppressor in HCC cells, and more importantly, the endosome-lysosome trafficking regulated by Vps34 has the potential to become a target pathway in HCC treatment.
Abstract
Purpose: The role of vacuolar protein sorting 34 (Vps34), an indispensable protein required for cell vesicular trafficking, in the biological behavior of hepatocellular carcinoma (HCC) has yet to be studied. Materials and methods: In the present study, the expression of Vps34 in HCC and the effect of Vps34 on HCC cell invasion was detected both in vivo and in vitro. Furthermore, by modulating the RILP and Rab11, which regulate juxtanuclear lysosome aggregation and recycling endosome respectively, the underlying mechanism was investigated. Results: Vps34 was significantly decreased in HCC and negatively correlated with the HCC invasiveness both in vivo and in vitro. Moreover, Vps34 could promote lysosomal juxtanuclear accumulation, reduce the invasive ability of HCC cells via the Rab7-RILP pathway. In addition, the deficiency of Vps34 in HCC cells affected the endosome-lysosome system, resulting in enhanced Rab11 mediated endocytic recycling of cell surface receptor and increased invasion of HCC cells. Conclusion: Our study reveals that Vps34 acts as an invasion suppressor in HCC cells, and more importantly, the endosome-lysosome trafficking regulated by Vps34 has the potential to become a target pathway in HCC treatment.
참고문헌 (30)
- Lindmo K, "Regulation of membrane traffic by phosphoinositide 3-kinases", J Cell Sci, 119, pp.605~614 (2006)
- Nobukuni T, "Amino acids mediate mTOR", raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase, 2005, pp.102, 14238~14243
- Lamb CA, "Endocytosis and autophagy : shared machinery for degradation", Bioessays, 35, pp.34~45 (2013)
- Perera RM, "The lysosome as a regulatory hub", Annu Rev Cell Dev Biol, 32, pp.223~253 (2016)
- Mellman I, "Endocytosis and cancer", Cold Spring Harb Perspect Biol, 5, pp.a016949~ (2013)
- Yu L, "Termination of autophagy and reformation of lysosomes regulated by mTOR", Nature, 465, pp.942~946 (2010)
- Wirth M, "Autophagosome formation : the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage", Semin Cancer Biol, 23, pp.301~309 (2013)
- Liang XH, "Induction of autophagy and inhibition of tumorigenesis by beclin 1", Nature, 402, pp.672~676 (1999)
- LI M, "Interpretation of guidelines for diagnosis and treatment of primary liver cancer(2017 edition)", Chin J Gen Surg, 28, pp.785~789 (2019)
- van Zijl F, "Initial steps of metastasis : cell invasion and endothelial transmigration", Mutat Res, 728, pp.23~34 (2011)
- Ma Y, "Expression of bone morphogenetic protein-2 and its receptors in epithelial ovarian cancer and their influence on the prognosis of ovarian cancer patients", J Exp Clin Cancer Res, 29, pp.85~ (2010)
- Ye QH, "GOLM1 modulates EGFR", RTK cell-surface recycling to drive hepatocellular carcinoma metastasis, 2016, pp.30, 444~458
- Yan Y, "Regulation of class III(Vps34)PI3Ks", Biochem Soc Trans, 35, pp.239~241 (2007)
- Hutagalung AH, "Role of Rab GTPases in membrane traffic and cell physiology", Physiol Rev, 91, pp.119~149 (2011)
- Al-Akhrass H, "Sortilin limits EGFR signaling by promoting its internalization in lung cancer", Nat Commun, 8, pp.1182~ (2017)
- Bechtel W, "Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis", J Am Soc Nephrol, 24, pp.727~743 (2013)
- Jaber N, "Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function", Proc Natl Acad Sci U S A, 109, pp.2003~2008 (2012)
- Zhou X, "Deletion of PIK3C3", Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway, 2010, pp.107, 9424~9429
- Korolchuk VI, "Lysosomal positioning coordinates cellular nutrient responses", Nat Cell Biol, 13, pp.453~460 (2011)
- Sabeh F, "Protease-dependent versus-independent cancer cell invasion programs : three-dimensional amoeboid movement revisited", J Cell Biol, 185, pp.11~19 (2009)
- Jordens I, "The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors", Curr Biol, 11, pp.1680~1685 (2001)
- Funderburk SF, "The Beclin 1-VPS34 complex : at the crossroads of autophagy and beyond", Trends Cell Biol, 20, pp.355~362 (2010)
- Itakura E, "Atg14 and UVRAG : mutually exclusive subunits of mammalian Beclin 1-PI3K complexes", Autophagy, 5, pp.534~536 (2009)
- Muller PA, "Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion", Oncogene, 32, pp.1252~1265 (2013)
- Muller PA, "Mutant p53 drives invasion by promoting integrin recycling", Cell, 139, pp.1327~1341 (2009)
- Ullrich O, "Rab11 regulates recycling through the pericentriolar recycling endosome", J Cell Biol, 135, pp.913~924 (1996)
- Dong Q, "Rab11a promotes proliferation and invasion through regulation of YAP in non-small cell lung cancer", Oncotarget, 8, pp.27800~27811 (2017)
- Gong X, "Rab11 Functions as an oncoprotein via nuclear factor kappa B(NF-kappaB)signaling pathway in human bladder carcinoma", Med Sci Monit, 24, pp.5093~5101 (2018)
- Zhu W, "The inhibitory effect of ECG and EGCG dimeric procyanidins on colorectal cancer cells growth is associated with their actions at lipid rafts and the inhibition of the epidermal growth factor receptor signaling", Biochem Pharmacol, 175, pp.113923~ (2020)
- Sheng W, "Musashi2 promotes EGF-induced EMT in pancreatic cancer via ZEB1-ERK", MAPK signaling, 2020, pp.39, 16~