Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

Kuang Tzu Huang; I. Ying Kuo; Ming Chao Tsai; Chun Hsien Wu; Li Wen Hsu; Li Yu Chen; Chao Pin Kung; Yu Fan Cheng; Shigeru Goto; Yu Wei Chou; Chao Long Chen; Chih Che Lin; Kuang Den Chen

doi:10.1016/j.omtn.2017.10.002

Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

Kuang Tzu Huang, I. Ying Kuo, Ming Chao Tsai, Chun Hsien Wu, Li Wen Hsu, Li Yu Chen, Chao Pin Kung, Yu Fan Cheng, Shigeru Goto, Yu Wei Chou, Chao Long Chen, Chih Che Lin, Kuang Den Chen

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

Original language	English
Pages (from-to)	274-283
Number of pages	10
Journal	Molecular Therapy - Nucleic Acids
Volume	9
DOIs	https://doi.org/10.1016/j.omtn.2017.10.002
Publication status	Published - 2017 Dec

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Huang, K. T., Kuo, I. Y., Tsai, M. C., Wu, C. H., Hsu, L. W., Chen, L. Y., Kung, C. P., Cheng, Y. F., Goto, S., Chou, Y. W., Chen, C. L., Lin, C. C., & Chen, K. D. (2017). Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma. Molecular Therapy - Nucleic Acids, 9, 274-283. https://doi.org/10.1016/j.omtn.2017.10.002

Huang, Kuang Tzu ; Kuo, I. Ying ; Tsai, Ming Chao ; Wu, Chun Hsien ; Hsu, Li Wen ; Chen, Li Yu ; Kung, Chao Pin ; Cheng, Yu Fan ; Goto, Shigeru ; Chou, Yu Wei ; Chen, Chao Long ; Lin, Chih Che ; Chen, Kuang Den. / Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma. In: Molecular Therapy - Nucleic Acids. 2017 ; Vol. 9. pp. 274-283.

@article{30779ee34e3a422096b7362e676881b3,

title = "Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma",

abstract = "Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.",

author = "Huang, {Kuang Tzu} and Kuo, {I. Ying} and Tsai, {Ming Chao} and Wu, {Chun Hsien} and Hsu, {Li Wen} and Chen, {Li Yu} and Kung, {Chao Pin} and Cheng, {Yu Fan} and Shigeru Goto and Chou, {Yu Wei} and Chen, {Chao Long} and Lin, {Chih Che} and Chen, {Kuang Den}",

note = "Funding Information: This work was supported by grants from the following sources: Ministry of Science and Technology of Taiwan (MOST 104-2314-B-182A-018 and MOST 105-2314-B-182A-037-MY2 to C.-L.C. and MOST 104-2314-B-182A-089-MY3 to Y.-F.C.) and Chang Gung Memorial Hospital (CMRPG8C1151, CMRPG8D1032, and CMRPG8D1033 to K.-T.H.; CMRPG8D0561, CMRPG8D0751, CMRPG8D1022, and CMRPG8D1023 to K.-D.C.; CMRPG8A1203 and CMRPG8E1651 to C.-C.L.; and CMRPG8C0952 and CMRPG8D1012 to C.-L.C.). We also thank the Tissue Bank Core Lab at Kaohsiung Chang Gung Memorial Hospital (CLRPG8B0033, CLRPG8E0161, and CMRPG8D0062 to Y.-W.C.) for excellent technical support.",

year = "2017",

month = dec,

doi = "10.1016/j.omtn.2017.10.002",

language = "English",

volume = "9",

pages = "274--283",

journal = "Molecular Therapy - Nucleic Acids",

issn = "2162-2531",

publisher = "Nature Publishing Group",

}

Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma. / Huang, Kuang Tzu; Kuo, I. Ying; Tsai, Ming Chao; Wu, Chun Hsien; Hsu, Li Wen; Chen, Li Yu; Kung, Chao Pin; Cheng, Yu Fan; Goto, Shigeru; Chou, Yu Wei; Chen, Chao Long; Lin, Chih Che; Chen, Kuang Den.

In: Molecular Therapy - Nucleic Acids, Vol. 9, 12.2017, p. 274-283.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

AU - Huang, Kuang Tzu

AU - Kuo, I. Ying

AU - Tsai, Ming Chao

AU - Wu, Chun Hsien

AU - Hsu, Li Wen

AU - Chen, Li Yu

AU - Kung, Chao Pin

AU - Cheng, Yu Fan

AU - Goto, Shigeru

AU - Chou, Yu Wei

AU - Chen, Chao Long

AU - Lin, Chih Che

AU - Chen, Kuang Den

N1 - Funding Information: This work was supported by grants from the following sources: Ministry of Science and Technology of Taiwan (MOST 104-2314-B-182A-018 and MOST 105-2314-B-182A-037-MY2 to C.-L.C. and MOST 104-2314-B-182A-089-MY3 to Y.-F.C.) and Chang Gung Memorial Hospital (CMRPG8C1151, CMRPG8D1032, and CMRPG8D1033 to K.-T.H.; CMRPG8D0561, CMRPG8D0751, CMRPG8D1022, and CMRPG8D1023 to K.-D.C.; CMRPG8A1203 and CMRPG8E1651 to C.-C.L.; and CMRPG8C0952 and CMRPG8D1012 to C.-L.C.). We also thank the Tissue Bank Core Lab at Kaohsiung Chang Gung Memorial Hospital (CLRPG8B0033, CLRPG8E0161, and CMRPG8D0062 to Y.-W.C.) for excellent technical support.

PY - 2017/12

Y1 - 2017/12

N2 - Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

AB - Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

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