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Published in: Tumor Biology 2/2016

01-02-2016 | Original Article

Low-level expression of microRNA-375 predicts poor prognosis in hepatocellular carcinoma

Authors: Na Zhou, Jinhua Wu, Xiang Wang, Zhao Sun, Qin Han, Lin Zhao

Published in: Tumor Biology | Issue 2/2016

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Abstract

MicroRNAs are predicted to play fundamental roles in the tumorigenesis of hepatocellular carcinoma (HCC). MiR-375 is frequently downregulated in HCC and acts as a tumor suppressor by targeting multiple oncogenes. The objective of this study was to evaluate miR-375 expression and its relevance to the prognosis of HCC. MiR-375 expression was measured in cancerous tissues using qRT-PCR and dichotomized based on a median cutoff. The association between miR-375 expression and clinicopathological parameters and prognosis was subsequently determined. Expression levels of miR-375 were detected in a cohort of 38 HCC patients who underwent curative surgery. No significant correlations were observed between miR-375 expression and clinicopathological parameters, such as gender, age, performance status, preoperative serum AFP level, histological grade, HBV-DNA copy number, ascites, cirrhosis, tumor size, number of tumor nodules, and macrovascular invasion. However, miR-375 expression differs across CLIP scores significantly (p < 0.05). A trend toward poorer disease-free survival (DFS) was observed in patients with lower miR-375 expression compared to those with higher miR-375 expression (p = 0.307). Multivariate analysis demonstrated that low miR-375 expression was an independent prognostic predictor for progression (p = 0.032, risk ratio 3.273). Subgroup analysis revealed that low expression of miR-375 was significantly associated with adverse DFS in patients with poorly differentiated histology, higher serum AFP level (≥400 ng/ml), and advanced tumor stage (CLIP score 1∼3) (p = 0.017, 0.009, and 0.024, respectively). Our study demonstrates that miR-375 expression is significantly correlated with DFS and may be a potential prognostic biomarker of disease progression in HCC.
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Literature
1.
go back to reference Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. Clin Oncol. 2006;24(14):2137–50.CrossRef Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. Clin Oncol. 2006;24(14):2137–50.CrossRef
2.
go back to reference Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed
3.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
4.
go back to reference Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48 Suppl 1:S20–37.CrossRefPubMed Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48 Suppl 1:S20–37.CrossRefPubMed
5.
6.
go back to reference Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30(6):1434–40.CrossRefPubMed Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30(6):1434–40.CrossRefPubMed
7.
go back to reference European Association For The Study Of The Liver. European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.CrossRef European Association For The Study Of The Liver. European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.CrossRef
8.
9.
go back to reference Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T. ShimotohnoK. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25(17):2537–45.CrossRefPubMed Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T. ShimotohnoK. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25(17):2537–45.CrossRefPubMed
10.
go back to reference Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47(6):1955–63.CrossRefPubMed Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47(6):1955–63.CrossRefPubMed
11.
go back to reference Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897–907.CrossRefPubMed Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897–907.CrossRefPubMed
12.
go back to reference Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27(43):5651–61.CrossRefPubMed Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27(43):5651–61.CrossRefPubMed
13.
go back to reference Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A. 2010;107(1):264–9.CrossRefPubMed Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A. 2010;107(1):264–9.CrossRefPubMed
14.
go back to reference Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinomacells. Cancer Res. 2009;69(14):5761–7.CrossRefPubMed Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinomacells. Cancer Res. 2009;69(14):5761–7.CrossRefPubMed
15.
go back to reference Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28(40):3526–36.CrossRefPubMedPubMedCentral Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28(40):3526–36.CrossRefPubMedPubMedCentral
16.
go back to reference Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122(8):2884–97.CrossRefPubMedPubMedCentral Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122(8):2884–97.CrossRefPubMedPubMedCentral
17.
go back to reference Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432(7014):226–30.CrossRefPubMed Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432(7014):226–30.CrossRefPubMed
18.
go back to reference Liu AM, Poon RT, Luk JM. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun. 2010;394(3):623–7.CrossRefPubMed Liu AM, Poon RT, Luk JM. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun. 2010;394(3):623–7.CrossRefPubMed
19.
go back to reference He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene. 2012;31(28):3357–69.CrossRefPubMed He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene. 2012;31(28):3357–69.CrossRefPubMed
20.
go back to reference Zhao J, Wang W, Huang Y, Wu J, Chen M, Cui P, et al. HBx elevates oncoprotein AEG-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes. DNA Cell Biol. 2014;33(10):715–22.CrossRefPubMed Zhao J, Wang W, Huang Y, Wu J, Chen M, Cui P, et al. HBx elevates oncoprotein AEG-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes. DNA Cell Biol. 2014;33(10):715–22.CrossRefPubMed
21.
go back to reference Yin J, Hou P, Wu Z, Wang T, Nie Y. Circulating miR-375 and miR-199a-3p as potential biomarkers for the diagnosis of hepatocellular carcinoma. Tumour Biol. 2015. [Epub ahead of print]. Yin J, Hou P, Wu Z, Wang T, Nie Y. Circulating miR-375 and miR-199a-3p as potential biomarkers for the diagnosis of hepatocellular carcinoma. Tumour Biol. 2015. [Epub ahead of print].
22.
go back to reference A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.Hepatology. 1998; 28(3): 751–5. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.Hepatology. 1998; 28(3): 751–5.
23.
go back to reference Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed
24.
25.
go back to reference Zhou J, Song S, He S, Zhu X, Zhang Y, Yi B, et al. MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. Int J Mol Med. 2014;33(4):950–6.PubMed Zhou J, Song S, He S, Zhu X, Zhang Y, Yi B, et al. MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. Int J Mol Med. 2014;33(4):950–6.PubMed
26.
go back to reference Mathé EA, Nguyen GH, Bowman ED, Zhao Y, Budhu A, Schetter AJ, et al. MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res. 2009;15(19):6192–200.CrossRefPubMedPubMedCentral Mathé EA, Nguyen GH, Bowman ED, Zhao Y, Budhu A, Schetter AJ, et al. MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res. 2009;15(19):6192–200.CrossRefPubMedPubMedCentral
27.
go back to reference Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70(6):2339–49.CrossRefPubMed Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70(6):2339–49.CrossRefPubMed
28.
go back to reference Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol. 2012;180(3):917–28.CrossRefPubMedPubMedCentral Harris T, Jimenez L, Kawachi N, Fan JB, Chen J, Belbin T, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol. 2012;180(3):917–28.CrossRefPubMedPubMedCentral
29.
go back to reference Chang C, Shi H, Wang C, Wang J, Geng N, Jiang X, et al. Correlation of microRNA-375 downregulation with unfavorable clinical outcome of patients with glioma. Neurosci Lett. 2012;531(2):204–8.CrossRefPubMed Chang C, Shi H, Wang C, Wang J, Geng N, Jiang X, et al. Correlation of microRNA-375 downregulation with unfavorable clinical outcome of patients with glioma. Neurosci Lett. 2012;531(2):204–8.CrossRefPubMed
30.
go back to reference Kowalik MA, Saliba C, Pibiri M, Perra A, Ledda-Columbano GM, Sarotto I, et al. Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice. Hepatology. 2011;53(6):2086–96.CrossRefPubMed Kowalik MA, Saliba C, Pibiri M, Perra A, Ledda-Columbano GM, Sarotto I, et al. Yes-associated protein regulation of adaptive liver enlargement and hepatocellular carcinoma development in mice. Hepatology. 2011;53(6):2086–96.CrossRefPubMed
31.
go back to reference Ho CM, Lee PH, Hu RH. Clinical correlation of miR-375 and alpha-fetoprotein in hepatocellular carcinoma: comparison in mice and humans. Hepatology. 2011;54(3):1105–6. author reply 1106.CrossRefPubMed Ho CM, Lee PH, Hu RH. Clinical correlation of miR-375 and alpha-fetoprotein in hepatocellular carcinoma: comparison in mice and humans. Hepatology. 2011;54(3):1105–6. author reply 1106.CrossRefPubMed
32.
go back to reference Ding L, Xu Y, Zhang W, Deng Y, Si M, Du Y, et al. MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2. Cell Res. 2010;20(7):784–93.CrossRefPubMed Ding L, Xu Y, Zhang W, Deng Y, Si M, Du Y, et al. MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2. Cell Res. 2010;20(7):784–93.CrossRefPubMed
33.
go back to reference Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, et al. MicroRNA-375 inhibits tumor growth and metastasis in esophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. Gut. 2012;61(1):33–42.CrossRefPubMed Kong KL, Kwong DL, Chan TH, Law SY, Chen L, Li Y, et al. MicroRNA-375 inhibits tumor growth and metastasis in esophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. Gut. 2012;61(1):33–42.CrossRefPubMed
34.
go back to reference Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111(1):379–82.CrossRefPubMed Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111(1):379–82.CrossRefPubMed
35.
go back to reference Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene. 2008;27(8):1114–21.CrossRefPubMed Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene. 2008;27(8):1114–21.CrossRefPubMed
36.
go back to reference Chang Y, Yan W, He X, Zhang L, Li C, Huang H, et al. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 2012;143(1):177–87.CrossRefPubMed Chang Y, Yan W, He X, Zhang L, Li C, Huang H, et al. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 2012;143(1):177–87.CrossRefPubMed
Metadata
Title
Low-level expression of microRNA-375 predicts poor prognosis in hepatocellular carcinoma
Authors
Na Zhou
Jinhua Wu
Xiang Wang
Zhao Sun
Qin Han
Lin Zhao
Publication date
01-02-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 2/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3841-0

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