Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition

Liu Xiao Yang, Qiang Gao, Jie Yi Shi, Zhi Chao Wang, Yong Zhang, Ping Ting Gao, Xiao Ying Wang, Ying Hong Shi, Ai Wu Ke, Guo Ming Shi, Jia Bin Cai, Wei Ren Liu, Meng Duan, Ying Jun Zhao, Yuan Ji, Dong Mei Gao, Kai Zhu, Jian Zhou, Shuang Jian Qiu, Ya Cao & 2 others Qi Qun Tang, Jia Fan

Research output: Contribution to journalArticle

Abstract

The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38/nuclear factor κB/snail pathway. We found that the tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. Conclusions: MAP3K4, significantly down-regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA.

Original languageEnglish (US)
Pages (from-to)1804-1816
Number of pages13
JournalHepatology
Volume62
Issue number6
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

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MAP Kinase Kinase Kinase 4
Epithelial-Mesenchymal Transition
Cholangiocarcinoma
Growth
Neoplasms
Neoplasm Metastasis
Mutation
Lymph Nodes
Placentation
Snails

ASJC Scopus subject areas

  • Hepatology

Cite this

Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition. / Yang, Liu Xiao; Gao, Qiang; Shi, Jie Yi; Wang, Zhi Chao; Zhang, Yong; Gao, Ping Ting; Wang, Xiao Ying; Shi, Ying Hong; Ke, Ai Wu; Shi, Guo Ming; Cai, Jia Bin; Liu, Wei Ren; Duan, Meng; Zhao, Ying Jun; Ji, Yuan; Gao, Dong Mei; Zhu, Kai; Zhou, Jian; Qiu, Shuang Jian; Cao, Ya; Tang, Qi Qun; Fan, Jia.

In: Hepatology, Vol. 62, No. 6, 01.12.2015, p. 1804-1816.

Research output: Contribution to journalArticle

Yang, LX, Gao, Q, Shi, JY, Wang, ZC, Zhang, Y, Gao, PT, Wang, XY, Shi, YH, Ke, AW, Shi, GM, Cai, JB, Liu, WR, Duan, M, Zhao, YJ, Ji, Y, Gao, DM, Zhu, K, Zhou, J, Qiu, SJ, Cao, Y, Tang, QQ & Fan, J 2015, 'Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition', Hepatology, vol. 62, no. 6, pp. 1804-1816. https://doi.org/10.1002/hep.28149
Yang, Liu Xiao ; Gao, Qiang ; Shi, Jie Yi ; Wang, Zhi Chao ; Zhang, Yong ; Gao, Ping Ting ; Wang, Xiao Ying ; Shi, Ying Hong ; Ke, Ai Wu ; Shi, Guo Ming ; Cai, Jia Bin ; Liu, Wei Ren ; Duan, Meng ; Zhao, Ying Jun ; Ji, Yuan ; Gao, Dong Mei ; Zhu, Kai ; Zhou, Jian ; Qiu, Shuang Jian ; Cao, Ya ; Tang, Qi Qun ; Fan, Jia. / Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition. In: Hepatology. 2015 ; Vol. 62, No. 6. pp. 1804-1816.
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abstract = "The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06{\%}) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38/nuclear factor κB/snail pathway. We found that the tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. Conclusions: MAP3K4, significantly down-regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA.",
author = "Yang, {Liu Xiao} and Qiang Gao and Shi, {Jie Yi} and Wang, {Zhi Chao} and Yong Zhang and Gao, {Ping Ting} and Wang, {Xiao Ying} and Shi, {Ying Hong} and Ke, {Ai Wu} and Shi, {Guo Ming} and Cai, {Jia Bin} and Liu, {Wei Ren} and Meng Duan and Zhao, {Ying Jun} and Yuan Ji and Gao, {Dong Mei} and Kai Zhu and Jian Zhou and Qiu, {Shuang Jian} and Ya Cao and Tang, {Qi Qun} and Jia Fan",
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T1 - Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition

AU - Yang, Liu Xiao

AU - Gao, Qiang

AU - Shi, Jie Yi

AU - Wang, Zhi Chao

AU - Zhang, Yong

AU - Gao, Ping Ting

AU - Wang, Xiao Ying

AU - Shi, Ying Hong

AU - Ke, Ai Wu

AU - Shi, Guo Ming

AU - Cai, Jia Bin

AU - Liu, Wei Ren

AU - Duan, Meng

AU - Zhao, Ying Jun

AU - Ji, Yuan

AU - Gao, Dong Mei

AU - Zhu, Kai

AU - Zhou, Jian

AU - Qiu, Shuang Jian

AU - Cao, Ya

AU - Tang, Qi Qun

AU - Fan, Jia

PY - 2015/12/1

Y1 - 2015/12/1

N2 - The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38/nuclear factor κB/snail pathway. We found that the tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. Conclusions: MAP3K4, significantly down-regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA.

AB - The molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood, and its incidence continues to increase worldwide. Deficiency of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) has been reported to induce the epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. MAP3K4 has somatic mutation in iCCA so we sequenced all exons of MAP3K4 in 124 iCCA patients. We identified nine somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that messenger RNA and protein levels of MAP3K4 were significantly reduced in iCCA versus paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, overexpression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of the p38/nuclear factor κB/snail pathway. We found that the tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. Conclusions: MAP3K4, significantly down-regulated, frequently mutated, and potently regulating the EMT process in iCCA, was a putative tumor suppressor of iCCA.

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