title: Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer.
abstract: Transforming growth factor β (TGF-β)/Smad signaling is involved in colorectal carcinoma (CRC) development and progression. The frequent loss of SMAD4 is associated with liver metastasis and poor prognosis of CRC, but the underlying mechanism remains elusive. This study aimed to elucidate the role of Smad-independent TGF-β signaling in CRC metastasis. Immunohistochemistry showed that Smad4 level was negatively correlated with TNM stage and phospho-ERK level in human CRCs and liver metastasis samples. Knockdown of Smad4 in CT26 and HCT116 cells activated ERK pathway, altered the expression of MMP2 and COX-2, promoted cell motility, migration, and invasion in vitro, enhanced metastasis, and shortened the survival of metastatic tumor-bearing mice. MEK inhibitor U0126 and GSK1120212 inhibited the motility, migration, and invasion of Smad4 knockdown cells, inhibited metastasis, and prolonged the survival of metastatic tumor-bearing mice. Furthermore, MEK inhibitor could reverse the changes of phospho-ERK, MMP2, and COX-2 levels. In conclusion, our results indicate that ERK pathway plays a key oncogenic role in CRC with SMAD4 inactivation mutations, and implicate ERK as a potential therapeutic target for CRC liver metastasis.
authors.affiliation: Hepatic Surgery Center; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Ai
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Guannan
authors.initials: G
authors.lastname: Jin
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhao
authors.forename: Jingjing
authors.initials: J
authors.lastname: Yu
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Lin
authors.forename: Wanguang
authors.initials: W
authors.lastname: Zhang
authors.forename: Huifang
authors.initials: H
authors.lastname: Liang
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Zhang
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051901:Smad4 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK pathway; Smad4; TGF-β; colorectal cancer; metastasis
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