Abstract
Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3β1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.
Highlights
Ovarian cancer is the leading cause of death among gynecologic cancers and the fifth most common cause of cancer related death in the United States
To evaluate the clinical significance of CD151 expression in human ovarian cancer, IHC analyses were conducted on a tumor tissue array (TMA) harboring normal ovarian tissue, as well as papillary serous adenocarcinomas varying in grade and metastatic status (Fig. 1A)
Since tetraspanin molecules like CD151 are known to function within tetraspaninenriched membrane microdomain (TEMM) [28, 29], we evaluated the impact of disrupting CD151 on the integrity of LB integrin-enriched protein complexes in ovarian cancer cells
Summary
Ovarian cancer is the leading cause of death among gynecologic cancers and the fifth most common cause of cancer related death in the United States. 70% of newly diagnosed ovarian tumors are in the late, metastatic stages of disease [1]. Treatment for serous (the most common cell type) ovarian cancer is surgical resection followed by combination platinum- and taxolbased chemotherapies. Despite the aggressive yet predictable route of tumor dissemination and high failure rate of current therapies, the molecular and cellular mechanisms underlying this cancer type remain poorly defined [4, 5]. A better mechanistic understanding of ovarian cancer progression and metastasis is urgently needed in order to develop more effective target-based therapies
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