Basic and Translational Science AbstractTGFBI-promoted Adhesion, Migration and Invasion of Human Renal Cell Carcinoma Depends on Inactivation of von Hippel-Lindau Tumor Suppressor
Section snippets
Cell Culture and Agents
Two RCC cell lines, ACHN (wild-type VHL) and A498 (null-type VHL), were obtained from American Type Culture Collection (Manassas, VA) and cultured in complete medium consisting of Roswell Park Memorial Institute-1640 medium (Gibco, Bio-cult, Glasgow, Scotland) supplemented with 25 mM HEPES, 2 mM l-glutamine, 1% nonessential amino acids, 100 U/mL penicillin, 100 μg/mL streptomycin, and 10% heat-inactivated fetal bovine serum. The cell lines were maintained as monolayers in 10-cm plastic dishes
VHL Inactivation Upregulated TGFBI Expression
To detect the association of VHL status and TGFBI expression, A498 cells were stably transfected with either the VHL vector or the blank vector lacking the VHL insert. The ACHN cells were transfected with either VHL siRNA or negative siRNA controls. Protein expression was evaluated by Western blots (Fig. 1A). The VHL-active RCC cell lines had high levels of VHL expression and low levels of HIF-1α, HIF-2α, and TGFBI. In contrast, the VHL-inactive RCC cell lines had low levels of VHL expression
Comment
The protein TGFBI was first detected in a human lung adenocarcinoma cell line after stimulation by TGF-β15 and has been found immunohistochemically in such human tissues as the cornea, skin, lung, bone, bladder, and kidney.16 Additionally, TGFBI is involved in such human diseases as corneal dystrophies,17 melorheostosis, osteogenesis,18 diabetic angiopathy, atherothrombosis, and restenosis.19 The protein TGFBI elicits numerous changes in cellular behavior that include differentiating epithelial
Conclusions
Both TGF-β1 and TGFBI expression could be suppressed by VHL. Because VHL mutations occur early in RCC development, inactivating VHL induces an important secondary genetic event in the TGFBI signaling pathway that could lead to the metastasis of RCC cells. These results indicate that blocking TGFBI might provide a novel treatment strategy and that the TGF-β1-TGFBI pathway might be an appropriate target to treat RCC with inactive VHL.
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2021, Cellular SignallingCitation Excerpt :Other in vitro studies focused on the prostate cancer tumor microenvironment demonstrated that signaling from the cytokine oncostatin M promotes TGFBI expression in mesenchymal stem cells more than cancer cells (Fig. 3) [56], but downstream effectors of oncostatin-M-induced TGFBI were not identified. In Renal Cell Carcinoma (RCC) cell lines, where the von Hippel-Lindau (VHL) plays a tumor suppressing role, VHL represses TGFBI expression and loss of VHL resulted in increased TGFBI levels, while rescuing VHL expression decreased TGFBI mRNA expression [64,71] in a HIF1-α independent manner [64]. In RCC, the VHL gene is often mutated [72] but whether mutated VHL leads to induction of TGFBI expression, is still unknown.
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Funding Support: Our research was supported by the National Natural Science Foundation of China (grant 30801139) and Basic-Clinical Research Foundation of Capital Medical University.
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Donghao Shang and Yuting Liu contributed equally to this work.