p53-p72-Δ225-331-V31I identified in a cholangiocarcinoma cell line promotes migration and invasiveness via the downregulation of claudin-1 expression and the activation of Cdc42

Abstract

TP53 is the most common gene mutated in human cancers, including in cholangiocarcinoma (CCA). The gain-of-function properties of p53 variants are often involved in cancer progression. The present study demon- strated that a truncated del p53 variant, del p53M213, exhibited gain-of-function properties and was highly expressed in the invasive liver fluke Opisthorchis viverrini-associated CCA cell line, KKU-M213. The del p53M213 variant lacked exons 7-9 and contained a V31I substitution (p53-p72-Δ225-331-V31I). Stably transfected p53-null human non-small cell lung H1299 cells exhibited a del p53M213 localization in both the cell cytosol and nucleus. Del p53M213 lacked anti-growth functions, and instead enhanced migration and invasiveness. In addition, this p53 variant downregulated claudin-1 expression and promoted Cdc42 activation, consistent with the roles of claudin-1 and Cdc42 in inhibiting cell-cell dissociation and promoting cell migration, respectively. On the whole, although del p53M213 is an important driver of cancer cell migration and invasiveness, other properties related to its novel gain-of-function properties require further investigation in order to develop effective treatment strategies for cancers bearing this truncated TP53 allele.