Cavin‐2 in oral cancer: A potential predictor for tumor progression

Abstract

Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc.

Cavin-2 Functions as a Suppressive Regulator in TNF-induced Mesenchymal Stromal Cell Inflammation and Angiogenic Phenotypes

“…Given the recognized contribution of MSC within (patho)physiological settings is currently of great interest towards either their therapeutic applications or as intermediates in solid tumour development, the dual roles of Caveolins and of Cavins must be better documented. Our study defines Cavin-2 as a putative suppressor regulator in TNF-mediated pro-inflammatory and pro-angiogenic conditions, and supports the recent evidence found in OSCC where its down-regulation was functionally and clinically linked to tumoural progression (36). …”

“…Cavin-2 was recently suggested to regulate Caveolin-1 expression, leading to slow oral squamous cell carcinoma (OSCC) proliferation by inactivation of the extracellular regulated kinase (ERK) pathway (36). Cavin-2 may therefore be a possible key regulator of OSCC progression via a Cavin-2/Caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs.…”

Prognostic and Diagnostic Significance of SDPR-Cavin-2 in Hepatocellular Carcinoma

“…Cavins play important roles in caveolae biogenesis, regulating caveolar function and organization [31]. Evidence showed that cavin-2 (serum deprivation protein response, SDPR) was present in many cellular types, and down-regulated in several different cancers including breast, gastric, kidney, prostate and oral cancer [28,32]. In 2016, Ozturk et al [27] found that cavin-2 could be a potential prognostic biomarker and a therapeutic target for breast cancer.…”

“…What is more, researchers suggested that transforming growth factor-β (TGF-β), which can induce EMT, was blocked by cavin-2 in breast cancer. In oral squamous cell carcinomas, Unozawa et al [32] suggested that the ERK signaling pathway was attenuated frequently in the overexpression cavin-2 cells. In studied cancers, cavin-2 was a metastasis suppressor by inhibiting EMT, migration, and intravasation accompanied with promotion of apoptosis [27].…”

Evidence for critical role of Tie2/Ang1 interaction in metastatic oral cancer

“…The protein concentration was measured using a commercial Bradford reagent (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Immunoblot analysis was performed as described previously (14,(34)(35)(36)(37). Briefly, protein extracts (20 µg) were electrophoresed on 4-12% Bis-Tris gel (Invitrogen; Thermo Fisher Scientific, Inc.), transferred to polyvinylidene fluoride membranes (Invitrogen; Thermo Fisher Scientific, Inc.), and blocked for 1 h at room temperature in Blocking One (Nacalai Tesque Inc., Kyoto, Japan).…”