Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway

Cancer Lett. 2015 Jan 28;356(2 Pt B):613-27. doi: 10.1016/j.canlet.2014.10.008. Epub 2014 Oct 8.


Cyclin-dependent kinase 8 (CDK8), a gene encoding the cyclin-dependent kinase (CDK) component of the Mediator complex, is known as a colon cancer oncogene. Our recent study showed that CDK8 plays an important role in the formation of pancreatic cancer, but the CDK8 expression levels were not completely identical in different pancreatic cancer samples. The level of CDK8 expression depended on whether the K-ras gene was mutated; its expression was much higher in samples carrying a K-ras mutation than in wild-type K-ras samples. Moreover, CDK8 expression was reduced following mutated K-ras knockdown in K-ras-mutated pancreatic cancer cells, whereas CDK8 expression was increased following expression of mutated K-ras in wild-type K-ras cells. Our study demonstrates that mutated K-ras stimulates CDK8 expression, possibly by regulating HIF-1α, and both CDK8 and mutated K-ras were confirmed to promote cell proliferation and prevent apoptosis in vitro. Additionally, we found that both CDK8 and mutated K-ras promote the invasion and migration of pancreatic cancer cells via the positive regulation of the Wnt/β-catenin signaling pathway, thereby increasing the expression of Snail1 and ZEB1, which act as important stimulating factors of the epithelial-to-mesenchymal transition (EMT). Finally, knockdown of either CDK8 or mutated K-ras contributed to attenuated pancreatic cancer growth in BALB/c nude mice. In conclusion, these findings demonstrate that mutated K-ras promotes CDK8 expression and that the regulatory effects of CDK8 on the EMT are partially attributed to the Wnt/β-catenin signaling pathway.

Keywords: CDK8; EMT; K-ras mutation; Pancreatic cancer; Wnt/β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Blotting, Western
  • Cell Movement
  • Cell Proliferation
  • Cyclin-Dependent Kinase 8 / genetics
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Epithelial-Mesenchymal Transition*
  • Fluorescent Antibody Technique
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Mice
  • Mice, Nude
  • Mutation / genetics*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Wnt Signaling Pathway*
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics*


  • AXIN2 protein, human
  • Axin Protein
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins