Skip to main content
Top
Published in: Cancer Cell International 1/2014

Open Access 01-12-2014 | Primary research

Decreased expression of the Nkx2.8 gene correlates with tumor progression and a poor prognosis in HCC cancer

Authors: Lei Qu, Biao Deng, Yue Zeng, Zhongwei Cao

Published in: Cancer Cell International | Issue 1/2014

Login to get access

Abstract

Background

Nkx2.8 (Nk2 homeobox 8) is a novel NK-2 gene family member that has been implicated in the progression of human cancer. Its role in the progression of HCC remains unknown. In this study, we investigated the expression levels and prognostic value of Nkx2.8 in hepatocellular carcinoma.

Methods

The expression of Nkx2.8 was determined by real-time quantitative RT-PCR (qRT-PCR) and immunochemistry in paired cancerous and non-cancerous tissues of 48 patients with HCC. The relationships between the Nkx2.8 expression levels, the clinicopathological characteristics and patient survival were analyzed. The effects of Nkx2.8 overexpression on cellular proliferation ability, including MTT and colony formation assays, were investigated.

Results

Nkx2.8 expression was significantly downregulated in HCC cancer tissues compared with adjacent non-cancerous tissues. Further immunohistochemical analysis showed low expression of Nkx2.8 in HCC cancer tissues, and the clinicopathological analysis showed that the Nkx2.8 mRNA and protein expression levels were significantly correlated with the TNM stage (p = 0.032; p = 0.026, respectively). Kaplan–Meier survival curves revealed that lower Nkx2.8 expression was associated with a poor overall survival in HCC patients (P = 0.00172). The overexpression of Nkx2.8 in HCC cell lines inhibits cell proliferation and colony formation.

Conclusions

Our data indicated that Nkx2.8 plays important roles in the development and progression of HCC and might be a valuable prognostic biomarker and potential therapeutic target for HCC.
Appendix
Available only for authorised users
Literature
2.
go back to reference Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin MW, Koo WH, Asian Oncology Summit: Management of hepatocellular carcinoma in Asia: consensus statement from the Asian oncology summit 2009. Lancet Oncol. 2009, 10: 1111-1118. 10.1016/S1470-2045(09)70241-4.CrossRefPubMed Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin MW, Koo WH, Asian Oncology Summit: Management of hepatocellular carcinoma in Asia: consensus statement from the Asian oncology summit 2009. Lancet Oncol. 2009, 10: 1111-1118. 10.1016/S1470-2045(09)70241-4.CrossRefPubMed
3.
go back to reference Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodés J, EASL Panel of Experts on HCC: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001, 35: 421-430. 10.1016/S0168-8278(01)00130-1.CrossRefPubMed Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodés J, EASL Panel of Experts on HCC: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001, 35: 421-430. 10.1016/S0168-8278(01)00130-1.CrossRefPubMed
4.
go back to reference Bosch FX, Ribes J, Diaz M, Cleries R: Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004, 127: S5-S16. 10.1053/j.gastro.2004.09.011.CrossRefPubMed Bosch FX, Ribes J, Diaz M, Cleries R: Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004, 127: S5-S16. 10.1053/j.gastro.2004.09.011.CrossRefPubMed
5.
go back to reference Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003, 9: 416-423. 10.1038/nm843.CrossRefPubMed Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW: Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003, 9: 416-423. 10.1038/nm843.CrossRefPubMed
6.
go back to reference Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX: Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology. 2008, 48: 1834-1842. 10.1002/hep.22531.CrossRefPubMed Sun BS, Dong QZ, Ye QH, Sun HJ, Jia HL, Zhu XQ, Liu DY, Chen J, Xue Q, Zhou HJ, Ren N, Qin LX: Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology. 2008, 48: 1834-1842. 10.1002/hep.22531.CrossRefPubMed
7.
go back to reference Su L, David M: Distinct mechanisms of STAT phosphorylation via the interferon-alpha/beta receptor. Selective inhibition of STAT3 and STAT5 by piceatannol. J Biol Chem. 2000, 275: 12661-12666. 10.1074/jbc.275.17.12661.CrossRefPubMed Su L, David M: Distinct mechanisms of STAT phosphorylation via the interferon-alpha/beta receptor. Selective inhibition of STAT3 and STAT5 by piceatannol. J Biol Chem. 2000, 275: 12661-12666. 10.1074/jbc.275.17.12661.CrossRefPubMed
8.
go back to reference Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, Clergue F, Poupon R, Barbu V, Rosmorduc O: Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005, 41: 307-314. 10.1002/hep.20538.CrossRefPubMed Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, Clergue F, Poupon R, Barbu V, Rosmorduc O: Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005, 41: 307-314. 10.1002/hep.20538.CrossRefPubMed
9.
go back to reference Yu C, Zhang Z, Liao W, Zhao X, Liu L, Wu Y, Liu Z, Li Y, Zhong Y, Chen K, Li J, Zhou F, Song L: The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway. Carcinogenesis. 2012, 33: 678-686. 10.1093/carcin/bgr321.CrossRefPubMed Yu C, Zhang Z, Liao W, Zhao X, Liu L, Wu Y, Liu Z, Li Y, Zhong Y, Chen K, Li J, Zhou F, Song L: The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway. Carcinogenesis. 2012, 33: 678-686. 10.1093/carcin/bgr321.CrossRefPubMed
10.
go back to reference Lin C, Song L, Gong H, Liu A, Lin X, Wu J, Li M, Li J: Nkx2-8 downregulation promotes angiogenesis and activates NF-kappaB in esophageal cancer. Cancer Res. 2013, 73: 3638-3648. 10.1158/0008-5472.CAN-12-4028.CrossRefPubMed Lin C, Song L, Gong H, Liu A, Lin X, Wu J, Li M, Li J: Nkx2-8 downregulation promotes angiogenesis and activates NF-kappaB in esophageal cancer. Cancer Res. 2013, 73: 3638-3648. 10.1158/0008-5472.CAN-12-4028.CrossRefPubMed
11.
go back to reference Harris T, Pan Q, Sironi J, Lutz D, Tian J, Sapkar J, Perez-Soler R, Keller S, Locker J: Both gene amplification and allelic loss occur at 14q13.3 in lung cancer. Clin Cancer Res. 2011, 17: 690-699. 10.1158/1078-0432.CCR-10-1892.CrossRefPubMedCentralPubMed Harris T, Pan Q, Sironi J, Lutz D, Tian J, Sapkar J, Perez-Soler R, Keller S, Locker J: Both gene amplification and allelic loss occur at 14q13.3 in lung cancer. Clin Cancer Res. 2011, 17: 690-699. 10.1158/1078-0432.CCR-10-1892.CrossRefPubMedCentralPubMed
12.
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: 69-90. 10.3322/caac.20107.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.CrossRefPubMed
13.
go back to reference Seeff LB, Hoofnagle JH: Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006, 25: 3771-3777. 10.1038/sj.onc.1209560.CrossRefPubMed Seeff LB, Hoofnagle JH: Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006, 25: 3771-3777. 10.1038/sj.onc.1209560.CrossRefPubMed
14.
go back to reference Kwon OS, Jung YK, Kim YS, Kim SG, Kim YS, Lee JI, Lee JW, Kim YS, Chun BC, Kim JH: Effect of alcohol on the development of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis: a cross-sectional case-control study. Korean J Hepatol. 2010, 16: 308-314. 10.3350/kjhep.2010.16.3.308.CrossRefPubMedCentralPubMed Kwon OS, Jung YK, Kim YS, Kim SG, Kim YS, Lee JI, Lee JW, Kim YS, Chun BC, Kim JH: Effect of alcohol on the development of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis: a cross-sectional case-control study. Korean J Hepatol. 2010, 16: 308-314. 10.3350/kjhep.2010.16.3.308.CrossRefPubMedCentralPubMed
15.
go back to reference Long XD, Yao JG, Zeng Z, Ma Y, Huang XY, Wei ZH, Liu M, Zhang JJ, Xue F, Zhai B, Xia Q: Polymorphisms in the coding region of X-ray repair complementing group 4 and aflatoxin B1-related hepatocellular carcinoma. Hepatology. 2013, 58: 171-181. 10.1002/hep.26311.CrossRefPubMed Long XD, Yao JG, Zeng Z, Ma Y, Huang XY, Wei ZH, Liu M, Zhang JJ, Xue F, Zhai B, Xia Q: Polymorphisms in the coding region of X-ray repair complementing group 4 and aflatoxin B1-related hepatocellular carcinoma. Hepatology. 2013, 58: 171-181. 10.1002/hep.26311.CrossRefPubMed
16.
go back to reference Blanpain C: Tracing the cellular origin of cancer. Nat Cell Biol. 2013, 15: 126-134. 10.1038/ncb2657.CrossRefPubMed Blanpain C: Tracing the cellular origin of cancer. Nat Cell Biol. 2013, 15: 126-134. 10.1038/ncb2657.CrossRefPubMed
17.
go back to reference Lapouge G, Youssef KK, Vokaer B, Achouri Y, Michaux C, Sotiropoulou PA, Blanpain C: Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci U S A. 2011, 108: 7431-7436. 10.1073/pnas.1012720108.CrossRefPubMedCentralPubMed Lapouge G, Youssef KK, Vokaer B, Achouri Y, Michaux C, Sotiropoulou PA, Blanpain C: Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci U S A. 2011, 108: 7431-7436. 10.1073/pnas.1012720108.CrossRefPubMedCentralPubMed
18.
go back to reference Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, Qin LX, Wu XZ: microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 2012, 30: 1321-1326.PubMed Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, Qin LX, Wu XZ: microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 2012, 30: 1321-1326.PubMed
19.
go back to reference Zhu HT, Dong QZ, Sheng YY, Wei JW, Wang G, Zhou HJ, Ren N, Jia HL, Ye QH, Qin LX: MicroRNA-29a-5p is a novel predictor for early recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. PLoS One. 2012, 7: e52393-10.1371/journal.pone.0052393.CrossRefPubMedCentralPubMed Zhu HT, Dong QZ, Sheng YY, Wei JW, Wang G, Zhou HJ, Ren N, Jia HL, Ye QH, Qin LX: MicroRNA-29a-5p is a novel predictor for early recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. PLoS One. 2012, 7: e52393-10.1371/journal.pone.0052393.CrossRefPubMedCentralPubMed
20.
go back to reference Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, Wang N, Niu Y, Wu Z, Zhou J, Qiu SJ, Shi YH, Yu B, Tang N, Chu W, Wang M, Wu J, Zhang Z, Yang S, Gu J, Wang H, Qin W: Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012, 13: 817-826. 10.1016/S1470-2045(12)70233-4.CrossRefPubMed Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, Wang N, Niu Y, Wu Z, Zhou J, Qiu SJ, Shi YH, Yu B, Tang N, Chu W, Wang M, Wu J, Zhang Z, Yang S, Gu J, Wang H, Qin W: Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012, 13: 817-826. 10.1016/S1470-2045(12)70233-4.CrossRefPubMed
21.
go back to reference Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L: Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology. 2012, 55: 483-490. 10.1002/hep.24703.CrossRefPubMedCentralPubMed Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L: Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology. 2012, 55: 483-490. 10.1002/hep.24703.CrossRefPubMedCentralPubMed
22.
go back to reference Apergis GA, Crawford N, Ghosh D, Steppan CM, Vorachek WR, Wen P, Locker J: A novel nk-2-related transcription factor associated with human fetal liver and hepatocellular carcinoma. J Biol Chem. 1998, 273: 2917-2925. 10.1074/jbc.273.5.2917.CrossRefPubMed Apergis GA, Crawford N, Ghosh D, Steppan CM, Vorachek WR, Wen P, Locker J: A novel nk-2-related transcription factor associated with human fetal liver and hepatocellular carcinoma. J Biol Chem. 1998, 273: 2917-2925. 10.1074/jbc.273.5.2917.CrossRefPubMed
23.
go back to reference Hsu DS, Acharya CR, Balakumaran BS, Riedel RF, Kim MK, Stevenson M, Tuchman S, Mukherjee S, Barry W, Dressman HK, Nevins JR, Powers S, Mu D, Potti A: Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer. Proc Natl Acad Sci U S A. 2009, 106: 5312-5317. 10.1073/pnas.0900827106.CrossRefPubMedCentralPubMed Hsu DS, Acharya CR, Balakumaran BS, Riedel RF, Kim MK, Stevenson M, Tuchman S, Mukherjee S, Barry W, Dressman HK, Nevins JR, Powers S, Mu D, Potti A: Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer. Proc Natl Acad Sci U S A. 2009, 106: 5312-5317. 10.1073/pnas.0900827106.CrossRefPubMedCentralPubMed
Metadata
Title
Decreased expression of the Nkx2.8 gene correlates with tumor progression and a poor prognosis in HCC cancer
Authors
Lei Qu
Biao Deng
Yue Zeng
Zhongwei Cao
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2014
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-14-28

Other articles of this Issue 1/2014

Cancer Cell International 1/2014 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine