Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.
Oncogene. 2018 Feb 15;37(7):912-923. doi: 10.1038/onc.2017.393. Epub 2017 Oct 23.
SRY (sex determining region Y)-box 9 (SOX9) is required for oncogenic Kras-mediated acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasias (PanINs) and ultimately pancreatic ductal adenocarcinoma (PDAC). However, how oncogenic Kras affects SOX9 activity is not yet understood, and SOX9-associated genes in PDAC are also unknown at all. Here, we investigated the mechanistic link between SOX9 and oncogenic Kras, studied biological function of SOX9, and identified SOX9-related genes and their clinical significance in patients with PDAC. Our studies reveal that oncogenic Kras induces SOX9 mRNA and protein expression as well as phosphorylated SOX9 expression in human pancreatic ductal progenitor cells (HPNE) and pancreatic ductal cells (HPDE). Moreover, oncogenic Kras promoted nuclear translocation and transcriptional activity of SOX9 in these cells. TAK1/IκBα/NF-κB pathway contributed to induction of SOX9 by oncogenic Kras, and SOX9 in turn enhanced NF-κB activation. SOX9 promoted the proliferation of HPNE and PDAC cells, and correlated with minichromosome maintenance complex components (MCMs) and mediator of DNA damage checkpoint 1 (MDC1) expression. The overexpressive MDC1 was associated with less perineural and lymph node invasion of tumors and early TNM-stage of patients. Our results indicate that oncogenic Kras induces constitutive activation of SOX9 in HPNE and HPDE cells, and Kras/TAK1/IκBα/NF-κB pathway and a positive feedback between SOX9 and NF-κB are involved in this inducing process. SOX9 accelerates proliferation of cells and affects MCMs and MDC1 expression. MDC1 is associated negatively with invasion and metastasis of PDAC.
性决定区 Y 框 9（SOX9）是癌基因 Kras 介导的腺泡到导管化生（ADM）、胰腺上皮内瘤变（PanIN）以及最终胰腺导管腺癌（PDAC）所必需的。然而，癌基因 Kras 如何影响 SOX9 的活性尚不清楚，PDAC 中与 SOX9 相关的基因也完全未知。在这里，我们研究了 SOX9 与癌基因 Kras 之间的机制联系，研究了 SOX9 的生物学功能，并鉴定了 PDAC 患者中与 SOX9 相关的基因及其临床意义。我们的研究表明，癌基因 Kras 诱导人胰腺导管祖细胞（HPNE）和胰腺导管细胞（HPDE）中 SOX9 的 mRNA 和蛋白质表达以及磷酸化 SOX9 的表达。此外，癌基因 Kras 促进了这些细胞中 SOX9 的核易位和转录活性。TAK1/IκBα/NF-κB 通路促进了癌基因 Kras 诱导的 SOX9 表达，而 SOX9 又增强了 NF-κB 的激活。SOX9 促进了 HPNE 和 PDAC 细胞的增殖，并与微小染色体维持复合物成分（MCMs）和 DNA 损伤检查点 1 （MDC1）的表达相关。过表达的 MDC1 与肿瘤的神经周围和淋巴结侵犯较少以及患者的早期 TNM 分期相关。我们的结果表明，癌基因 Kras 诱导 HPNE 和 HPDE 细胞中 SOX9 的组成性激活，并且 Kras/TAK1/IκBα/NF-κB 通路和 SOX9 与 NF-κB 之间的正反馈参与了这一诱导过程。SOX9 加速细胞增殖，并影响 MCMs 和 MDC1 的表达。MDC1 与 PDAC 的侵袭和转移呈负相关。
