MiR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4

Hsin Yi Chen, Yu Min Lin, Hsiang Ching Chung, Yaw Dong Lang, Ching Jung Lin, John Huang, Wei Chi Wang, Feng Mao Lin, Zhen Chen, Hsien Da Huang, John Y J Shyy, Jin Tung Liang, Ruey Hwa Chen

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107-mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis.

Original languageEnglish
Pages (from-to)3631-3641
Number of pages11
JournalCancer Research
Volume72
Issue number14
DOIs
Publication statusPublished - Jul 15 2012
Externally publishedYes

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Death-Associated Protein Kinases
Colorectal Neoplasms
Neoplasm Metastasis
Down-Regulation
Cell-Matrix Junctions
MicroRNAs
Cell Adhesion
Cell Movement
Lymph Nodes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

MiR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. / Chen, Hsin Yi; Lin, Yu Min; Chung, Hsiang Ching; Lang, Yaw Dong; Lin, Ching Jung; Huang, John; Wang, Wei Chi; Lin, Feng Mao; Chen, Zhen; Huang, Hsien Da; Shyy, John Y J; Liang, Jin Tung; Chen, Ruey Hwa.

In: Cancer Research, Vol. 72, No. 14, 15.07.2012, p. 3631-3641.

Research output: Contribution to journalArticle

Chen, HY, Lin, YM, Chung, HC, Lang, YD, Lin, CJ, Huang, J, Wang, WC, Lin, FM, Chen, Z, Huang, HD, Shyy, JYJ, Liang, JT & Chen, RH 2012, 'MiR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4', Cancer Research, vol. 72, no. 14, pp. 3631-3641. https://doi.org/10.1158/0008-5472.CAN-12-0667
Chen, Hsin Yi ; Lin, Yu Min ; Chung, Hsiang Ching ; Lang, Yaw Dong ; Lin, Ching Jung ; Huang, John ; Wang, Wei Chi ; Lin, Feng Mao ; Chen, Zhen ; Huang, Hsien Da ; Shyy, John Y J ; Liang, Jin Tung ; Chen, Ruey Hwa. / MiR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. In: Cancer Research. 2012 ; Vol. 72, No. 14. pp. 3631-3641.
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AU - Chung, Hsiang Ching

AU - Lang, Yaw Dong

AU - Lin, Ching Jung

AU - Huang, John

AU - Wang, Wei Chi

AU - Lin, Feng Mao

AU - Chen, Zhen

AU - Huang, Hsien Da

AU - Shyy, John Y J

AU - Liang, Jin Tung

AU - Chen, Ruey Hwa

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AB - Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell-matrix adhesion and decreased cell-cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107-mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107-mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis.

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