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Oncogene. 2018 Feb 15;37(7):912-923. doi: 10.1038/onc.2017.393. Epub 2017 Oct 23.

SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer.

Zhou H1,2, Qin Y3,4, Ji S3,4, Ling J1, Fu J1, Zhuang Z1,5, Fan X1, Song L6, Yu X3,4, Chiao PJ1,7.

Author information

1
Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
2
Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China.
3
Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
4
Pancreatic Cancer Institute, Fudan University, Shanghai, China.
5
Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
6
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan Province, China.
7
The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.

Abstract

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.

PMID:
29059173
DOI:
10.1038/onc.2017.393
[Indexed for MEDLINE]

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