Keratins that are overexpressed selectively in human
carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of
keratin-17 (K17) predicts poor outcome in patients with
cervical cancer, at early or late stages of disease, surpassing in accuracy either
tumor staging or loss of p27(KIP1) as a negative prognostic marker in this setting. We investigated the mechanistic basis for the
biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and
pancreatic cancer cells. Specifically, we determined that K17 functions as an
oncoprotein by regulating the subcellular localization and degradation of p27(KIP1). We found that K17 was released from intermediate filaments and translocated into the nucleus via a
nuclear localization signal (NLS), specific among
keratins, where it bound p27(KIP1) during G1 phase of the cell cycle. p27(KIP1) lacks a
nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a
leucine-rich NES that mediated CRM1 binding for export.
Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27(KIP1), whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27(KIP1). In clinical specimens of
cervical cancer, we confirmed that the expressions of K17 and p27(KIP1) were inversely correlated, both across
tumors and within individual
tumors. Overall, our findings establish that K17 functions specially among
keratins as an
oncoprotein by controlling the ability of p27(KIP1) to influence
cervical cancer pathogenesis.