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Keratin 17: Cervical Cancer Prognostic Marker Promotes p27‐Nuclear Export and Tumor Growth

Recently, we identified keratin 17 (K17) as a negative prognostic marker for cervical cancer and based on preliminary data, we set out to determine if K17 is related to tumor stage and sustained proliferation. K17 and tumor suppressor p27 were detected by immunohistochemistry in cervical cancer specimens and multivariate survival analysis was conducted. Loss and gain of function approaches were performed by in vitro and in vivo by RNAi and transgenic expression of wild type and mutant K17 in cervical cancer cell lines. The five‐year survival for low K17 cervical cancer cases was 90% versus 52% for high K17 cases; the differences were consistent across low and high stage groups. K17 expression promoted cell proliferation and tumor growth and silencing of K17 induced G1 arrest and decreased tumor mass by nuclear stabilization of p27, a key regulator of G1/S transition. During G1, K17 was found in the nucleus bound to nuclear p27. Nuclear p27 was lost in cells expressing wild‐type K17 but nuclear p27 levels were 3‐fold higher in cells expressing K17 with either mutated nuclear localization signal (NLS) or mutated nuclear export signal (NES). To our knowledge, this is the first report of the presence of NLS and NES in any keratin. Finally, we determined that K17 and p27 are inversely expressed in human cervical cancer specimens, intratumorally and intertumorally. These data suggest a model in which nuclear K17 acts as an oncoprotein regulating sustained proliferation in cancer cells by acting as a bridge between p27 and Exportin 1 binding, controlling nuclear export and degradation of p27, contributing to poor patient outcome of cervical cancer patients.