Loss of p27Kip1 promotes metaplasia in the pancreasviathe regulation of Sox9 expression

Abstract

ABSTRACTp27 Kip1 (p27) is a negative regulator of proliferation and a tumor suppressor via the inhibition of cyclin-CDK activity in the nucleus. p27 is also involved in the regulation of other cellular processes, including transcription by acting as a transcriptional co-repressor. Loss of p27 expression is frequently observed in pancreatic adenocarcinomas in human and is associated with decreased patient survival. Similarly, in a mouse model of K-Ras-driven pancreatic cancer, loss of p27 accelerates tumor development and shortens survival, suggesting an important role for p27 in pancreatic tumorigenesis. Here, we sought to determine how p27 might contribute to early events leading to tumor development in the pancreas. We found that K-Ras activation in the pancreas causes p27 mislocalization at pre-neoplastic stages. Moreover, loss of p27 or expression of a mutant p27 that does not bind cyclinCDKs causes the mislocalization of several acinar polarity markers associated with metaplasia and induces the nuclear expression of Sox9 and Pdx1 two transcription factors involved in acinar-to-ductal metaplasia. Finally, we found that p27 directly represses transcription of Sox9, but not that of Pdx1. Thus, our results suggest that K-Ras activation, the earliest known event in pancreatic carcinogenesis, may cause loss of nuclear p27 expression which results in derepression of Sox9, triggering reprogrammation of acinar cells and metaplasia.

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…Nuclear CDKN1B suppresses the expression of key factors that regulate acinar cell dedifferentiation and transdifferentiation to a ductal phenotype, such as the transcription factors SOX9 and PDX1 (REF. 45). KRAS activation can decrease nuclear CDKN1B localization, which increases the expression of both SOX9 and PDX1.…”

Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma

“…In models of quiescent mouse fibroblasts, p27 was shown to interact with transcription factors and regulatory proteins to indirectly repress the transcription of genes involved in RNA splicing, mitochondrial organization and respiration, translation and cell cycle (Pippa et al 2012). In mouse exocrine pancreas, p27 suppresses the transcription of Sox9, a gene involved in acinar-to-ductal metaplasia (Jeannot et al 2015). Similar to these models, p27 might therefore act as transcriptional regulator in neuroendocrine cells and such regulatory function could be dose dependent and tissue specific.…”

SOX9 as one of the central units of regulation axis of pancreas embryogenesis and cancer progression

“…При запуске АПМ в ацинарных клетках происходит активация факторов транскрипции SOX9, Pdx1, Hnf6, Hnf1β, Hes1, характерных для бипотентных прогениторных клеток [66][67][68], а также факторов Klf4 и Klf5 [69,70]. Для ряда из них, например Klf4, Klf5, Pdx1 и Hnf6, в серии работ была показана их роль в возникновении АПМ и ее прогрессии в ПАПЖ [68][69][70][71][72], но особое внимание уделяется SOX9 и многочисленным способам активации его гена (рис.…”

“…Одной из наиболее частых причин возникновения ПАПЖ являются онкогенные мутации гена Kras, приводящие к тому, что его белковый продукт находится в состоянии постоянной функциональной активности [73]. На фоне этого происходит инактивация фактора p27 -репрессора гена SOX9 [66] и запускается NFκB-сигнальный путь, способствующий активации гена SOX9 [74]. Дополнительным фактором активации SOX9 при мутациях Kras может выступать и активация гена Klf5 [70].…”

“…Адаптировано из [62,66,70,74,76,77,79,81,82]. Толстыми прямыми стрелками указаны этапы превращения клеток.…”