Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

Tsai, Cheng-Lung; Cheng, Hung-Chi; Wang, Yu-Shiuan; Lin, Pei; Jen, Chauying J.; Kuo, I-Ying; Chang, Ying-Hua; Liao, Pao‐Chi; Chen, Ruey‐Hwa; Yuan, Wei-Chien; Hsu, Han‐Shui; Yang, Muh‐Hwa; Hsu, Ming; Wu, Chuyi; Wang, Yi‐Ching

doi:10.1038/ncomms5804

Cited by 50 publications

(56 citation statements)

References 46 publications

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“…Rab37 was found by Tsai's group downregulated in lung cancer patients with metastasis, which was associated with the worse outcome. Further investigation revealed that Rab37 targeted tissue TIMP-1 for exocytosis and in turn inhibits cancer metastasis [22]. Additionally, Okon and his colleagues found that Rab7 inhibited angiogenesis through regulating neuropilin-1 degradation in lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 97%

Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway

2015

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Rab31 belongs to the Ras superfamily of small GTP-binding proteins, which has been found to regulate the vesicle transport from the Golgi apparatus to early and late endosomes. The investigation here detected the expression of Rab31 in 96 patients with hepatocellular carcinoma (HCC) and tried to identify its significance on outcome of HCCs after liver resection. By immunohistochemistry staining, it was found that Rab31 expression in HCC tissues was remarkably higher than that in adjacent liver tissues. Aberrant Rab31 overexpression in HCC tissues was identified to be associated with worse prognosis after liver resection. Univariate analysis showed that advanced tumor-nodes-metastasis (TNM) staging of HCC, intrahepatic metastases, portal vein invasion, and higher Rab31 were the predictive factors of poor prognosis. Multivariate analysis demonstrated that intrahepatic metastases and higher Rab31 were the independent prognostic factors. Furthermore, forced expression of Rab31 in Huh7 cells was found to promote cell growth via upregulation of Bcl-2/BAX ratio induced by PI3K/AKT. Correspondingly, silencing Rab31 induced cell apoptosis and in turn suppressed the growth capacity of MHCC97 cells in vitro. Taken together, this study provides the evidence of Rab31 overexpression in HCC, and Rab31 is potentially used as a novel biomarker of poor prognosis in patients with HCC. PI3K/AKT/Bcl-2/BAX axis was involved in Rab31-promoting HCC progression.

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Section: Discussionmentioning

confidence: 97%

Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway

2015

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“…We previously reported that Rab37 was a metastasis suppressor . Here, we provide compelling evidence from cell‐based, animal and clinical studies that Rab37 functions as a modulator of macrophage polarization via regulating the exocytosis of sST2, resulting in the preferential shift of macrophages phenotype from M2‐like to M1‐like, and thereby inhibiting tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…The stable empty vector (EV), Rab37‐wild type (WT), GTP‐bound constitutive active (Q89L) or GDP‐bound dominant negative (T43N) cells were generated as described previously . The shRNA lentivirus for Rab knockdown, shRab#1, shRab#2 or sh‐ST2 was obtained from the National RNAi core Facility (Institute of Molecular Biology, Academia Sinica, Taiwan).…”

Section: Methodsmentioning

confidence: 99%

“…Low level of Rab37 mRNA expression was associated with tumor metastasis . We also showed that the small GTPase Rab37 regulates exocytosis of tumor cells to suppress metastasis by inhibiting cell motility through tissue inhibitor of metalloproteinase 1 (TIMP1) secretion and blocking neovasculature by releasing thrombospondin‐1 (TSP1) . These results suggest that Rab37 mediates the cross‐talk between cancer cells and their surrounding stroma via exocytosis of specific cargos.…”

Section: Introductionmentioning

confidence: 99%

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Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Tzeng

Chang

et al. 2018

Intl Journal of Cancer

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Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In our study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2 and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth.

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“…Furthermore, Rab 25 and chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by regulating the recycling of α5β1 integrin from late endosomes to the plasma membrane [160]. In contrast, Rab37 suppresses tumour metastasis by exocytosis of the tissue inhibitor of metalloproteinase 1 (TIMP1), thereby inhibiting matrix metalloproteinase 9 (MMP9) [161]. Finally, Rab18 is highly expressed in Hepatitis B virus (HBV)-associated HCC tissue and upregulated Rab18 is mediated by HBV X protein, which promotes hepatoma cell proliferation [162].…”

Section: The Role Of Gtpase During Cytokinesis and Viral Buddingmentioning

confidence: 99%

Cyclophilin function in Cancer; lessons from virus replication

Lavin¹

2015

CMP

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Cyclophilins belong to a group of proteins that possess peptidyl prolyl isomerase activity and catalyse the cis-trans conversion of proline peptide bonds. Cyclophilin members play important roles in protein folding and as molecular chaperones, in addition to a wellestablished role as host factors required for completion of the virus life cycle. Members of the cyclophilin family are overexpressed in a range of human malignancies including hepatocellular cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, colorectal cancer and glioblastoma multiforme, however, their precise role in tumourigenesis remains unclear. In recent years, mounting evidence supports a role for prolyl isomerisation during mammalian cell division; a process with striking similarity to plasma membrane remodelling during virus replication. Here we will summarise our current understanding of the role of cyclophilins in cancer. We will review the function of cyclophilins during mammalian cell division and during HIV-1 infection, and highlight common processes involving members of the ESCRT and Rab GTPase families. IntroductionThe interconversion of protein backbone between cis and trans, catalysed by peptidyl prolyl isomerases (PPIases), is an important event that alters protein structure and activity and regulates a wide spectrum of cellular functions in normal physiological processes. For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5]. As a result, isomerases have gained significant interest as therapeutic targets in the treatment of these diseases.

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Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

Cited by 50 publications

References 46 publications

Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway

Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Cyclophilin function in Cancer; lessons from virus replication

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