Downregulation of Rab17 promotes cell proliferation and invasion in non‐small cell lung cancer through STAT3/HIF‐1α/VEGF signaling

Abstract

Background: Rab GTPases play a key role in regulating intercellular vesicle trafficking in both exo-and endocytic pathways. Recent studies have reported that Rab small GTPases and the associated regulatory proteins and effectors are involved in many cancers. The purpose of this study was to investigate the biological role of Rab17 in non-small cell lung cancer (NSCLC) and the relative mechanism. Methods: Rab17 expression in human NSCLC cell lines and tissues was evaluated using real-time PCR (RT-PCR), western blot and immunohistochemical (IHC) staining. NSCLC cell lines with RAB17 stable knockdown were generated to explore its function in vitro and in vivo. Additionally, we investigated the potential mechanism of Rab17 by identifying the expression levels of STAT3/ HIF-1α/VEGF pathway using western blot analysis. Results: Decreased Rab17 expression was correlated with poor overall survival in NSCLC patients. The functional assays showed that knockdown of Rab17 could promote tumorigenic properties of NSCLC cells in vitro and in vivo, including enhanced cell proliferation, colony formation, invasion and migration, angiogenesis and tumor xenograft growth, and suppressed apoptosis. Moreover, Rab17 downregulation decreased epithelial marker E-cadherin and increased mesenchymal markers Vimentin and β-catenin, suggesting knockdown of Rab17 induced epithelial-mesenchymal transition (EMT). Conclusion: Downregulation of Rab17 promotes cell invasion and enhances tumorigenicity in part through the STAT3/HIF-1α/VEGF pathway, which may represent a novel potential therapeutic target.

<p>Resveratrol Suppresses Tumor Progression via Inhibiting STAT3/HIF-1α/VEGF Pathway in an Orthotopic Rat Model of Non-Small-Cell Lung Cancer (NSCLC)</p>

“…32,34 More importantly, some recent studies have revealed that the STAT3/ HIF-1α/VEGF pathway was activated in NSCLC. 11,12,35 The relationship between STAT3 expression and apoptosis had been reported in many studies. Generally, while the expression, production, phosphorylation, or activation of STAT3 was found in various cancer cells, the apoptosis process in these cells was inhibited.…”

“…6 It has been reported that the STAT3/HIF-1α/VEGF pathway was closely associated with tumorigenesis and progress of various tumors, including hepatocellular carcinoma, gastroenteropancreatic neuroendocrine tumor, hemangioma, malignant peripheral nerve sheath tumor, and NSCLC. 7,12 Resveratrol (trans-3,4′,5-trihydroxystilbene, RES), a natural polyphenolic compound, is found in a large number of edible plants, especially grapes and peanuts. 13 Numerous studies have demonstrated its diverse pharmacological activities, such as immune regulation, neuroprotection, antioxidant and anti-inflammatory properties.…”

A Positive Feedback Loop of lncRNA DSCR8/miR-98-5p/STAT3/HIF-1α Plays a Role in the Progression of Ovarian Cancer

“…Moreover, HIF-1α enhances the invasion and migration of OC cells induced by hypoxia ( 33 ). Interestingly, STAT3 promotes the expression of HIF-1α as its upstream molecule ( 17 , 34 ). Here, we found that overexpressing DSCR8 greatly promoted the activation of STAT3/HIF-1α, while overexpressing miR-98-5p reduced STAT3 expression and activation, indicating that DSCR8/miR-98-5p regulates OC development by regulating STAT3/HIF-1α pathway.…”

“…Studies have found that miRNA cluster MC-let-7a-1∼let-7d regulates glioma autophagy and apoptosis by targeting STAT3 ( 16 ). Besides, hypoxia inducible factor 1 alpha (HIF-1α), a prime modulator of cellular and systemic homeostatic response to hypoxia, can be activated by STAT3 and then regulate tumorigenesis ( 17 ). Here, our previous study demonstrates that lncRNA DSCR8 is upregulated in OC.…”

Comprehensive Analysis of Expression, Clinicopathological Association and Potential Prognostic Significance of RABs in Pancreatic Cancer

“…Further, the role of RABs in the shedding of extracellular vesicles has also been reported [ 55 , 56 , 57 , 58 ]. Aberrant expression of RABs is reported in various cancers, and they are shown to act either as a tumor promoter or suppressor in a context-dependent manner [ 59 , 60 , 61 , 62 , 63 ].…”