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Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.

ABSTRACT: Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins ?3?1 and ?6?1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of ?3 expression but requires PKC?, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.

SUBMITTER: Palmer TD

PROVIDER: S-EPMC3947299 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.

Palmer Trenis D TD Martínez Carlos H CH Vasquez Catalina C Hebron Katie E KE Jones-Paris Celestial C Arnold Shanna A SA Chan Susanne M SM Chalasani Venu V Gomez-Lemus Jose A JA Williams Andrew K AK Chin Joseph L JL Giannico Giovanna A GA Ketova Tatiana T Lewis John D JD Zijlstra Andries A

Cancer research 20131112 1

Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrat ...[more]

PMID: 24220242

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Project description:Owing to the complexity of interacting molecular networks on the cell surface, integrin-associated tetraspanin CD151 remains controversial regarding its clinical importance and functional impact in prostate cancer. The current study evaluated dynamics and clinical importance of CD151 expression and its function in prostate cancer by IHC analysis of two independent patient cohorts (n=80, 181), bioinformatic interrogation of the TCGA database, and evaluation of gene knockdown effect at the cellular level. Our data showed that aside from high mRNA expression, CD151 was primarily localized to intercellular junctions at the plasma membrane in normal prostate glands or benign tissues, regardless of nature of antibodies used. By contrast, in primary tumors from patients with metastatic disease, CD151 was largely localized in the cytosol. Furthermore, the level of the cell-cell junction-linked CD151 was inversely associated with Gleason grade and tumor stage (P<0.001 for both). The portion of primary tumors expressing junctional CD151 was also three-fold less in the metastatic patient population than its counterpart (P<0.001). In line with these observations, CD151 and its associated ?3?1 or ?6?4 integrin inversely correlated with androgen receptor (AR) at the mRNA level (Spearman coefficient: -0.44, -0.48 and -0.42) in the TCGA cohort. Expression of these adhesion molecules also correlated with DNA methylation in their promoters (Spearman coefficient: -0.37, -0.71 and -0.82). Combined, these data suggest that CD151 and associated integrins are linked to tumor metastasis through AR and the epigenetic program. Meanwhile, CD151 knockdown in E-cadherin-positive tumor cells led to increased cell proliferation and induction of the epithelial-mesenchymal transition (EMT)-like phenotype. Given the strong RGD-binding integrin dependence of EMT-featured tumor cells, we examined focal adhesion kinase (FAK), their key signaling effector, in the above patient cohorts. In contrast to CD151, FAK exhibited positive correlation with tumor grade and stage as well as AR and p53 inactivation at either mRNA, protein or genomic level. Taken together, our results suggest that CD151 represses prostate cancer by antagonizing cell proliferation, EMT and the signaling of RGD-binding integrins. Since this anti-tumorigenic role is prone to the AR-mediated transcriptional and epigenetic regulation, CD151 and possibly ?3?1 and ?6?4 integrins are of potential biomarkers for metastatic prostate cancer.

Dataset Information

Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.

Publications

Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.

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