Downregulation of Tumor Suppressor Gene Spurs Development of Ovarian Cancer

Researchers studying ovarian cancer have identified a tumor suppressor gene that has significantly lowered expression in ovarian cancer cells, and which may be a useful diagnostic and therapeutic marker for the disease.

Investigators at the Medical University of Vienna (Austria) focused on the hVps37A gene which produces a protein described as a member of the membrane-trafficking ESCRT-I (endosomal sorting complex required for transport-I) complex that mediates the internalization and degradation of ubiquitinated membrane receptors.

In the current study, the investigators used a tetracycline inducible ovarian cancer cell-culture model to show the effects of hVps37A knockdown in vitro and in vivo. In addition, they studied the effects of the epidermal growth factor receptor (EGFR) inhibitors cetuximab and lapatinib on ovarian cancer cells under conditions of hVps37A knockdown.

Results published in the December 15, 2011, edition of the journal Clinical Cancer Research revealed that hVps37A was significantly downregulated in ovarian cancer and modified the prognostic value of EGFR and HER2 (human epidermal growth factor receptor 2) expression. In addition, hVps37A downregulation in ovarian cancer cells led to cytoplasmic EGFR retention and hyperactivation of downstream pathways and was associated with enhanced xenograft growth in nude mice and invasion of the collagen matrix. In other words, the activated form of EGFR was not degraded and continued to affect greatly subsequent cellular processes - something that hVps37A would have inhibited. Furthermore, hVps37A-deficient cells became irresponsive to inhibition by the therapeutic antibody cetuximab.

Senior author Dr. Michael Krainer, professor of oncology at the Medical University of Vienna, said, “Our results, which are based on an unparalleled number of tissue samples from ovarian cancer, clearly confirm a significant reduction of hVps37A activity. At the same time, we found that this reduced activity strongly influences the activity of the membrane receptor EGFR. This is an essential indication of the function of hVps37A - and of the importance of our results for other cancer types, in which EGFR activity causes cancer to develop.”

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