Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells

Stella Chai; Kai Yu Ng; Man Tong; Eunice Y. Lau; Kin Wah Lee; Kwok Wah Chan; Yun Fei Yuan; Tan To Cheung; Siu Tim Cheung; Xiao Qi Wang; Nathalie Wong; Chung Mau Lo; Kwan Man; Xin Yuan Guan; Stephanie Ma

doi:10.1002/hep.28821

Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells

Stella Chai, Kai Yu Ng, Man Tong, Eunice Y. Lau, Kin Wah Lee, Kwok Wah Chan, Yun Fei Yuan, Tan To Cheung, Siu Tim Cheung, Xiao Qi Wang, Nathalie Wong, Chung Mau Lo, Kwan Man, Xin Yuan Guan, Stephanie Ma

Research output: Journal article publication › Journal article › Academic research › peer-review

164 Citations (Scopus)

Abstract

Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).

Original language	English
Pages (from-to)	2062-2076
Number of pages	15
Journal	Hepatology
Volume	64
Issue number	6
DOIs	https://doi.org/10.1002/hep.28821
Publication status	Published - 1 Dec 2016

ASJC Scopus subject areas

Hepatology

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10.1002/hep.28821

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title = "Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells",

abstract = "Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).",

author = "Stella Chai and Ng, {Kai Yu} and Man Tong and Lau, {Eunice Y.} and Lee, {Kin Wah} and Chan, {Kwok Wah} and Yuan, {Yun Fei} and Cheung, {Tan To} and Cheung, {Siu Tim} and Wang, {Xiao Qi} and Nathalie Wong and Lo, {Chung Mau} and Kwan Man and Guan, {Xin Yuan} and Stephanie Ma",

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doi = "10.1002/hep.28821",

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T1 - Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells

AU - Chai, Stella

AU - Ng, Kai Yu

AU - Tong, Man

AU - Lau, Eunice Y.

AU - Lee, Kin Wah

AU - Chan, Kwok Wah

AU - Yuan, Yun Fei

AU - Cheung, Tan To

AU - Cheung, Siu Tim

AU - Wang, Xiao Qi

AU - Wong, Nathalie

AU - Lo, Chung Mau

AU - Man, Kwan

AU - Guan, Xin Yuan

AU - Ma, Stephanie

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).

AB - Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).

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DO - 10.1002/hep.28821

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SN - 0270-9139

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JO - Hepatology

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Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells

Abstract

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