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Erschienen in:

06.09.2018 | Original Article

Rab23 Promotes Hepatocellular Carcinoma Cell Migration Via Rac1/TGF-β Signaling

verfasst von: Li Zhang, Bingqiang Zhang, Wenxian You, Pan Li, Youlin Kuang

Erschienen in: Pathology & Oncology Research | Ausgabe 1/2020

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Abstract

Rab23 is a member of Ras-related small GTPase family, which plays a critical role in the progression of wide range of tumors. However, its biological function in hepatocellular carcinoma still remains unclear. Here, we investigated the effects of Rab23 on proliferation and migration in hepatocellular carcinoma cell and its potential mechanisms. We found over-expression of Rab23 promoted the Hep3B hepatocellular carcinoma cell migration, which could be reversed by Rab23 silencing. Rab23 induced Rac1 activation and followed progression of epithelial-mesenchymal transition (EMT) along with upregulation of N-cadherin, snail as well as vimentin and downregulation of E-cadherin via upregulating Transforming Growth Factor-β (TGF-β). Silencing Rac1 significantly attenuated Rab23-induced HepG2 migration and TGF-β. Moreover, knockdown of TGF-β effectively attenuated Rab23-induced EMT. Taken together, we demonstrated a mechanistic cascade of Rab23 enhangcing Rac1 activation and subsequent TGF-β expression, leading to hepatocellular carcinoma cell migration.
Literatur
1.
Zurück zum Zitat Massarweh NN, El-Serag HB (2017) Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Control 24:1073274817729245CrossRef Massarweh NN, El-Serag HB (2017) Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Control 24:1073274817729245CrossRef
2.
Zurück zum Zitat Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. In: Lancet, vol 379, (London), pp 1245–1255 Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. In: Lancet, vol 379, (London), pp 1245–1255
3.
Zurück zum Zitat Delevoye C, Goud B (2015) Rab GTPases and kinesin motors in endosomal trafficking. Methods Cell Biol 130:235–246CrossRef Delevoye C, Goud B (2015) Rab GTPases and kinesin motors in endosomal trafficking. Methods Cell Biol 130:235–246CrossRef
4.
Zurück zum Zitat Eggenschwiler JT, Espinoza E, Anderson KV (2001) Rab23 is an essential negative regulator of the mouse sonic hedgehog signalling pathway. Nature 412:194–198CrossRef Eggenschwiler JT, Espinoza E, Anderson KV (2001) Rab23 is an essential negative regulator of the mouse sonic hedgehog signalling pathway. Nature 412:194–198CrossRef
5.
Zurück zum Zitat Cai ZZ, Xu LB, Cai JL, Wang JS, Zhou B, Hu H (2015) Inactivation of Rab23 inhibits the invasion and motility of pancreatic duct adenocarcinoma. Genet Mol Res 14:2707–2715CrossRef Cai ZZ, Xu LB, Cai JL, Wang JS, Zhou B, Hu H (2015) Inactivation of Rab23 inhibits the invasion and motility of pancreatic duct adenocarcinoma. Genet Mol Res 14:2707–2715CrossRef
6.
Zurück zum Zitat Jiang Y, Han Y, Sun C, Han C, Han N, Zhi W, Qiao Q (2016) Rab23 is overexpressed in human bladder cancer and promotes cancer cell proliferation and invasion. Tumour Biol 37:8131–8138CrossRef Jiang Y, Han Y, Sun C, Han C, Han N, Zhi W, Qiao Q (2016) Rab23 is overexpressed in human bladder cancer and promotes cancer cell proliferation and invasion. Tumour Biol 37:8131–8138CrossRef
7.
Zurück zum Zitat Wang M, Dong Q, Wang Y (2016) Rab23 is overexpressed in human astrocytoma and promotes cell migration and invasion through regulation of Rac1. Tumour Biol 37:11049–11055CrossRef Wang M, Dong Q, Wang Y (2016) Rab23 is overexpressed in human astrocytoma and promotes cell migration and invasion through regulation of Rac1. Tumour Biol 37:11049–11055CrossRef
8.
Zurück zum Zitat Hou Q, Wu YH, Grabsch H, Zhu Y, Leong SH, Ganesan K, Cross D, Tan LK, Tao J, Gopalakrishnan V, Tang BL, Kon OL, Tan P (2008) Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer. Cancer Res 68:4623–4630CrossRef Hou Q, Wu YH, Grabsch H, Zhu Y, Leong SH, Ganesan K, Cross D, Tan LK, Tao J, Gopalakrishnan V, Tang BL, Kon OL, Tan P (2008) Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer. Cancer Res 68:4623–4630CrossRef
9.
Zurück zum Zitat Denning KM, Smyth PC, Cahill SF, Finn SP, Conlon E, Li J, Flavin RJ, Aherne ST, Guenther SM, Ferlinz A, O'Leary JJ, Sheils OM (2007) A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples. Mod Pathol 20:1095–1102CrossRef Denning KM, Smyth PC, Cahill SF, Finn SP, Conlon E, Li J, Flavin RJ, Aherne ST, Guenther SM, Ferlinz A, O'Leary JJ, Sheils OM (2007) A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples. Mod Pathol 20:1095–1102CrossRef
10.
Zurück zum Zitat Liu YJ, Wang Q, Li W, Huang XH, Zhen MC, Huang SH, Chen LZ, Xue L, Zhang HW (2007) Rab23 is a potential biological target for treating hepatocellular carcinoma. World J Gastroenterol 13:1010–1017CrossRef Liu YJ, Wang Q, Li W, Huang XH, Zhen MC, Huang SH, Chen LZ, Xue L, Zhang HW (2007) Rab23 is a potential biological target for treating hepatocellular carcinoma. World J Gastroenterol 13:1010–1017CrossRef
11.
Zurück zum Zitat Jansen S, Gosens R, Wieland T, Schmidt M (2017) Paving the rho in cancer metastasis: rho GTPases and beyond. Pharmacol Ther Jansen S, Gosens R, Wieland T, Schmidt M (2017) Paving the rho in cancer metastasis: rho GTPases and beyond. Pharmacol Ther
12.
Zurück zum Zitat Bid HK, Roberts RD, Manchanda PK, Houghton PJ (2013) RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther 12:1925–1934CrossRef Bid HK, Roberts RD, Manchanda PK, Houghton PJ (2013) RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther 12:1925–1934CrossRef
13.
Zurück zum Zitat Melzer C, Hass R, von der Ohe J, Lehnert H, Ungefroren H (2017) The role of TGF-beta and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma. Cell Commun Signal 15:19CrossRef Melzer C, Hass R, von der Ohe J, Lehnert H, Ungefroren H (2017) The role of TGF-beta and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma. Cell Commun Signal 15:19CrossRef
14.
Zurück zum Zitat Liu Y, Zeng C, Bao N, Zhao J, Hu Y, Li C, Chi S (2015) Effect of Rab23 on the proliferation and apoptosis in breast cancer. Oncol Rep 34:1835–1844CrossRef Liu Y, Zeng C, Bao N, Zhao J, Hu Y, Li C, Chi S (2015) Effect of Rab23 on the proliferation and apoptosis in breast cancer. Oncol Rep 34:1835–1844CrossRef
15.
Zurück zum Zitat Cheng L, Yang F, Zhou B, Yang H, Yuan Y, Li X, Han S (2016) RAB23, regulated by miR-92b, promotes the progression of esophageal squamous cell carcinoma. Gene 595:31–38CrossRef Cheng L, Yang F, Zhou B, Yang H, Yuan Y, Li X, Han S (2016) RAB23, regulated by miR-92b, promotes the progression of esophageal squamous cell carcinoma. Gene 595:31–38CrossRef
16.
Zurück zum Zitat Jian Q, Miao Y, Tang L, Huang M, Yang Y, Ba W, Liu Y, Chi S, Li C (2016) Rab23 promotes squamous cell carcinoma cell migration and invasion via integrin beta1/Rac1 pathway. Oncotarget 7:5342–5352PubMed Jian Q, Miao Y, Tang L, Huang M, Yang Y, Ba W, Liu Y, Chi S, Li C (2016) Rab23 promotes squamous cell carcinoma cell migration and invasion via integrin beta1/Rac1 pathway. Oncotarget 7:5342–5352PubMed
17.
Zurück zum Zitat Zhang XY, Mu JH, Liu LY, Zhang HZ (2017) Upregulation of miR-802 suppresses gastric cancer oncogenicity via targeting RAB23 expression. Eur Rev Med Pharmacol Sci 21:4071–4078PubMed Zhang XY, Mu JH, Liu LY, Zhang HZ (2017) Upregulation of miR-802 suppresses gastric cancer oncogenicity via targeting RAB23 expression. Eur Rev Med Pharmacol Sci 21:4071–4078PubMed
18.
Zurück zum Zitat Dong C, Du Q, Wang Z, Wang Y, Wu S, Wang A (2016) MicroRNA-665 suppressed the invasion and metastasis of osteosarcoma by directly inhibiting RAB23. Am J Transl Res 8:4975–4981PubMedPubMedCentral Dong C, Du Q, Wang Z, Wang Y, Wu S, Wang A (2016) MicroRNA-665 suppressed the invasion and metastasis of osteosarcoma by directly inhibiting RAB23. Am J Transl Res 8:4975–4981PubMedPubMedCentral
19.
Zurück zum Zitat Katz LH, Li Y, Chen JS, Munoz NM, Majumdar A, Chen J, Mishra L (2013) Targeting TGF-beta signaling in cancer. Expert Opin Ther Targets 17:743–760CrossRef Katz LH, Li Y, Chen JS, Munoz NM, Majumdar A, Chen J, Mishra L (2013) Targeting TGF-beta signaling in cancer. Expert Opin Ther Targets 17:743–760CrossRef
20.
Zurück zum Zitat Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L, Reddy EP (2009) Liver stem cells and hepatocellular carcinoma. Hepatology (Baltimore, MD) 49:318–329CrossRef Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L, Reddy EP (2009) Liver stem cells and hepatocellular carcinoma. Hepatology (Baltimore, MD) 49:318–329CrossRef
21.
Zurück zum Zitat Meindl-Beinker NM, Matsuzaki K, Dooley S (2012) TGF-beta signaling in onset and progression of hepatocellular carcinoma. In: Digestive Diseases, vol 30, (Basel), pp 514–523 Meindl-Beinker NM, Matsuzaki K, Dooley S (2012) TGF-beta signaling in onset and progression of hepatocellular carcinoma. In: Digestive Diseases, vol 30, (Basel), pp 514–523
22.
Zurück zum Zitat Wendt MK, Tian M, Schiemann WP (2012) Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res 347:85–101CrossRef Wendt MK, Tian M, Schiemann WP (2012) Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res 347:85–101CrossRef
23.
Zurück zum Zitat Caja L, Bertran E, Campbell J, Fausto N, Fabregat I (2011) The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J Cell Physiol 226:1214–1223CrossRef Caja L, Bertran E, Campbell J, Fausto N, Fabregat I (2011) The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J Cell Physiol 226:1214–1223CrossRef
Metadaten
Titel
Rab23 Promotes Hepatocellular Carcinoma Cell Migration Via Rac1/TGF-β Signaling
verfasst von
Li Zhang
Bingqiang Zhang
Wenxian You
Pan Li
Youlin Kuang
Publikationsdatum
06.09.2018
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 1/2020
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-018-0463-z

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