Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction
MicroRNA-122 (miR-122) is implicated as a regulator of physiological and pathophysiological processes in the liver. Overexpression of Gα12 is associated with overall survival in patients with hepatocellular carcinoma (HCC). Array-based miRNA profiling was performed on Huh7 stably transfected with activated Gα12 to find miRNAs regulated by the Gα12 pathway; among them, miR-122 was most greatly repressed. miR-122 directly inhibits c-Met expression, playing a role in HCC progression. Gα12 destabilized HNF4α by accelerating ubiquitination, impeding constitutive expression of miR-122. miR-122 mimic transfection diminished the ability of Gα12 to increase c-Met and to activate ERK, STAT3, and Akt/mTOR, suppressing cell proliferation with augmented apoptosis. Consistently, miR-122 transfection prohibited tumor cell colony formation and endothelial tube formation. In a xenograft model, Gα12 knockdown attenuated c-Met expression by restoring HNF4α levels, and elicited tumor cell apoptosis but diminished Ki67 intensities. In human HCC samples, Gα12 levels correlated to c-Met and were inversely associated with miR-122. Both miR-122 and c-Met expression significantly changed in tumor node metastasis (TNM) stage II/III tumors. Moreover, changes in Gα12 and miR-122 levels discriminated recurrence-free and overall survival rates of HCC patients. Collectively, Gα12 overexpression in HCC inhibits MIR122 transactivation by inactivating HNF4α, which causes c-Met induction, contributing to cancer aggressiveness.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
Oncotarget - 6(2015), 22 vom: 07. Aug., Seite 19055-69 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Yoon Mee [VerfasserIn] |
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| Anmerkungen: |
Date Completed 28.06.2016 Date Revised 13.11.2018 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM248932950 |
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| 245 | 1 | 0 | |a Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction |
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| 520 | |a MicroRNA-122 (miR-122) is implicated as a regulator of physiological and pathophysiological processes in the liver. Overexpression of Gα12 is associated with overall survival in patients with hepatocellular carcinoma (HCC). Array-based miRNA profiling was performed on Huh7 stably transfected with activated Gα12 to find miRNAs regulated by the Gα12 pathway; among them, miR-122 was most greatly repressed. miR-122 directly inhibits c-Met expression, playing a role in HCC progression. Gα12 destabilized HNF4α by accelerating ubiquitination, impeding constitutive expression of miR-122. miR-122 mimic transfection diminished the ability of Gα12 to increase c-Met and to activate ERK, STAT3, and Akt/mTOR, suppressing cell proliferation with augmented apoptosis. Consistently, miR-122 transfection prohibited tumor cell colony formation and endothelial tube formation. In a xenograft model, Gα12 knockdown attenuated c-Met expression by restoring HNF4α levels, and elicited tumor cell apoptosis but diminished Ki67 intensities. In human HCC samples, Gα12 levels correlated to c-Met and were inversely associated with miR-122. Both miR-122 and c-Met expression significantly changed in tumor node metastasis (TNM) stage II/III tumors. Moreover, changes in Gα12 and miR-122 levels discriminated recurrence-free and overall survival rates of HCC patients. Collectively, Gα12 overexpression in HCC inhibits MIR122 transactivation by inactivating HNF4α, which causes c-Met induction, contributing to cancer aggressiveness | ||
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| 700 | 1 | |a Lee, Chan Gyu |e verfasserin |4 aut | |
| 700 | 1 | |a Koo, Ja Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Tae Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jung Min |e verfasserin |4 aut | |
| 700 | 1 | |a An, Jihyun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kang Mo |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Sang Geon |e verfasserin |4 aut | |
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