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

Oncogene volume 37, pages 912–923 (2018)Cite this article

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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.

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Acknowledgements

We thank Dr Jun Yao in the Department of Biostatistics, MD Anderson Cancer Center, for statistical analysis of data from RNA-seq. This work was supported in part by grants from Skip Viragh foundation (to PJC), the National Cancer Institute (CA109405 and CA142674 to PJC), a Cancer Center Core Supporting grant (CA16672) and China National Natural Science Foundation (81272733).

Author contributions

HZ: study design, carrying out of experiments, analysis of data and manuscript writing; YQ: carrying out of experiments and technical support; SJ: analysis of data and material support; JL, JF, XF, ZZ, LS: technical support; PJC, XY: study supervision and manuscript writing.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Centre, Houston, TX, USA

    H Zhou, J Ling, J Fu, Z Zhuang, X Fan & P J Chiao

  2. Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China

    H Zhou

  3. Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Y Qin, S Ji & X Yu

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, China

    Y Qin, S Ji & X Yu

  5. Department of General Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China

    Z Zhuang

  6. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Henan Province, China

    L Song

  7. The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    P J Chiao

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  1. H Zhou
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Correspondence to X Yu or P J Chiao.

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Zhou, H., Qin, Y., Ji, S. et al. SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. Oncogene 37, 912–923 (2018). https://doi.org/10.1038/onc.2017.393

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