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

H. Zhou, Y. Qin, S. Ji, J. Ling, J. Fu, Z. Zhuang, X. Fan, L. Song, X. Yu, P. J. Chiao

Research output: Contribution to journalArticle

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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/I? Bα/NF-? B pathway contributed to induction of SOX9 by oncogenic Kras, and SOX9 in turn enhanced NF-? B 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/I? Bα/NF-? B pathway and a positive feedback between SOX9 and NF-? B 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.

Original languageEnglish (US)
Pages (from-to)912-923
Number of pages12
JournalOncogene
Volume37
Issue number7
DOIs
StatePublished - Feb 15 2018

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Pancreatic Neoplasms
DNA Damage
Adenocarcinoma
Maintenance
Mediator Complex
Metaplasia
Genes
Neoplasms
Stem Cells
Lymph Nodes
Cell Proliferation
Neoplasm Metastasis
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. / Zhou, H.; Qin, Y.; Ji, S.; Ling, J.; Fu, J.; Zhuang, Z.; Fan, X.; Song, L.; Yu, X.; Chiao, P. J.

In: Oncogene, Vol. 37, No. 7, 15.02.2018, p. 912-923.

Research output: Contribution to journalArticle

Zhou, H. ; Qin, Y. ; Ji, S. ; Ling, J. ; Fu, J. ; Zhuang, Z. ; Fan, X. ; Song, L. ; Yu, X. ; Chiao, P. J. / SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. In: Oncogene. 2018 ; Vol. 37, No. 7. pp. 912-923.
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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/I? Bα/NF-? B pathway contributed to induction of SOX9 by oncogenic Kras, and SOX9 in turn enhanced NF-? B 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/I? Bα/NF-? B pathway and a positive feedback between SOX9 and NF-? B 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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T1 - SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer

AU - Zhou, H.

AU - Qin, Y.

AU - Ji, S.

AU - Ling, J.

AU - Fu, J.

AU - Zhuang, Z.

AU - Fan, X.

AU - Song, L.

AU - Yu, X.

AU - Chiao, P. J.

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