Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway

Po Chen Chu, Peng-Chan Lin, Hsing Yu Wu, Kuen Tyng Lin, Christina Wu, Tanios Bekaii-Saab, Yih-Jyh Lin, Chung-Ta Lee, Jenq-Chang Lee, Ching Shih Chen

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.

Original languageEnglish
Pages (from-to)3440-3455
Number of pages16
JournalOncogene
Volume37
Issue number25
DOIs
Publication statusPublished - 2018 Jun 1

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Y-Box-Binding Protein 1
IGF Type 1 Receptor
Mitogen-Activated Protein Kinase Kinases
Colorectal Neoplasms
Neoplasm Metastasis
Liver
Standard of Care
Epigenomics
Carcinogenesis
Up-Regulation
Animal Models
Pharmacology
Gene Expression
Recurrence
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Chu, Po Chen ; Lin, Peng-Chan ; Wu, Hsing Yu ; Lin, Kuen Tyng ; Wu, Christina ; Bekaii-Saab, Tanios ; Lin, Yih-Jyh ; Lee, Chung-Ta ; Lee, Jenq-Chang ; Chen, Ching Shih. / Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway. In: Oncogene. 2018 ; Vol. 37, No. 25. pp. 3440-3455.
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abstract = "Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.",
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Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway. / Chu, Po Chen; Lin, Peng-Chan; Wu, Hsing Yu; Lin, Kuen Tyng; Wu, Christina; Bekaii-Saab, Tanios; Lin, Yih-Jyh; Lee, Chung-Ta; Lee, Jenq-Chang; Chen, Ching Shih.

In: Oncogene, Vol. 37, No. 25, 01.06.2018, p. 3440-3455.

Research output: Contribution to journalArticle

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AU - Chu, Po Chen

AU - Lin, Peng-Chan

AU - Wu, Hsing Yu

AU - Lin, Kuen Tyng

AU - Wu, Christina

AU - Bekaii-Saab, Tanios

AU - Lin, Yih-Jyh

AU - Lee, Chung-Ta

AU - Lee, Jenq-Chang

AU - Chen, Ching Shih

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AB - Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.

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