Abstract
Our microRNA (miRNA) expression signatures of hypopharyngeal squamous cell carcinoma, maxillary sinus squamous cell carcinoma and esophageal squamous cell carcinoma revealed that miR-375 was significantly reduced in cancer tissues compared with normal epithelium. In this study, we focused on the functional significance of miR-375 in cancer cells and identification of miR-375-regulated novel cancer networks in head and neck squamous cell carcinoma (HNSCC). Restoration of miR-375 showed significant inhibition of cell proliferation and induction of cell apoptosis in SAS and FaDu cell lines, suggesting that miR-375 functions as a tumor suppressor. We adopted genome-wide gene expression analysis to search for miR-375-regulated molecular targets. Gene expression data and luciferase reporter assays revealed that AEG-1/MTDH was directly regulated by miR-375. Cancer cell proliferation was significantly inhibited in HNSCC cells transfected with si-AEG-1/MTDH. In addition, expression levels of AEG-1/MTDH were significantly upregulated in cancer tissues. Therefore, AEG-1/MTDH may function as an oncogene in HNSCC. The identification of novel tumor suppressive miRNA and its regulated cancer pathways could provide new insights into potential molecular mechanisms of HNSCC oncogenesis.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Accession codes
References
Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010).
Hardisson, D. Molecular pathogenesis of head and neck squamous cell carcinoma. Eur. Arch. Otorhinolaryngol. 260, 502–508 (2003).
Leemans, C. R., Braakhuis, B. J. & Brakenhoff, R. H. The molecular biology of head and neck cancer. Nat. Rev. Cancer 11, 9–22 (2011).
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 9, 102–114 (2008).
Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866 (2006).
Esquela-Kerscher, A. & Slack, F. J. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).
Chiyomaru, T., Enokida, H., Tatarano, S., Kawahara, K., Uchida, Y., Nishiyama, K. et al. miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer. Br. J. Cancer 102, 883–891 (2010).
Ichimi, T., Enokida, H., Okuno, Y., Kunimoto, R., Chiyomaru, T., Kawamoto, K. et al. Identification of novel microRNA targets based on microRNA signatures in bladder cancer. Int. J. Cancer 125, 345–352 (2009).
Kano, M., Seki, N., Kikkawa, N., Fujimura, L., Hoshino, I., Akutsu, Y. et al. miR-145, miR-133a and miR-133b: tumor suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int. J. Cancer 127, 2804–2814 (2010).
Kikkawa, N., Hanazawa, T., Fujimura, L., Nohata, N., Suzuki, H., Chazono, H. et al. miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC). Br. J. Cancer 103, 877–884 (2010).
Yoshino, H., Chiyomaru, T., Enokida, H., Kawakami, K., Tatarano, S., Nishiyama, K. et al. The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. Br. J. Cancer 104, 808–818 (2011).
Mutallip, M., Nohata, N., Hanazawa, T., Kikkawa, N., Horiguchi, S., Fujimura, L. et al. Glutathione S-transferase P1 (GSTP1) suppresses cell apoptosis and its regulation by miR-133alpha in head and neck squamous cell carcinoma (HNSCC). Int. J. Mol. Med. 27, 345–352 (2011).
Nohata, N., Hanazawa, T., Kikkawa, N., Mutallip, M., Fujimura, L., Yoshino, H. et al. Caveolin-1 mediates tumor cell migration and invasion and its regulation by miR-133a in head and neck squamous cell carcinoma. Int. J. Oncol. 38, 209–217 (2011).
Nohata, N., Sone, Y., Hanazawa, T., Fuse, M., Kikkawa, N., Yoshino, H. et al. miR-1 as a tumor suppressive microRNA targeting TAGLN2 in head and neck squamous cell carcinoma. Oncotarget 2, 29–44 (2011).
Avissar, M., Christensen, B. C., Kelsey, K. T. & Marsit, C. J. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin. Cancer Res. 15, 2850–2855 (2009).
Hui, A. B., Lenarduzzi, M., Krushel, T., Waldron, L., Pintilie, M., Shi, W. et al. Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clin. Cancer Res. 16, 1129–1139 (2010).
Tsukamoto, Y., Nakada, C., Noguchi, T., Tanigawa, M., Nguyen, L. T., Uchida, T. et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 70, 2339–2349 (2010).
Liu, A. M., Poon, R. T. & Luk, J. M. MicroRNA-375 targets Hippo-signaling effector YAP in liver cancer and inhibits tumor properties. Biochem. Biophys. Res. Commun. 394, 623–627 (2010).
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. 20, 784–793 (2010).
Li, X., Lin, R. & Li, J. Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. Dig. Dis. Sci. (e-pub ahead of print 30 April 2011; PMID: 21533613).
Sugimoto, T., Seki, N., Shimizu, S., Kikkawa, N., Tsukada, J., Shimada, H. et al. The galanin signaling cascade is a candidate pathway regulating oncogenesis in human squamous cell carcinoma. Genes Chromosomes Cancer 48, 132–142 (2009).
Hu, G., Wei, Y. & Kang, Y. The multifaceted role of MTDH/AEG-1 in cancer progression. Clin. Cancer Res. 15, 5615–5620 (2009).
Sarkar, D., Emdad, L., Lee, S. G., Yoo, B. K., Su, Z. Z. & Fisher, P. B. Astrocyte elevated gene-1: far more than just a gene regulated in astrocytes. Cancer Res. 69, 8529–8535 (2009).
Almeida, M. I., Reis, R. M. & Calin, G. A. MicroRNA history: discovery, recent applications, and next frontiers. Mutat. Res. (e-pub ahead of print 30 March 2011; PMID: 21458467).
Tran, N., O’Brien, C. J., Clark, J. & Rose, B. Potential role of micro-RNAs in head and neck tumorigenesis. Head Neck 32, 1099–1111 (2010).
Glazer, C. A., Chang, S. S., Ha, P. K. & Califano, J. A. Applying the molecular biology and epigenetics of head and neck cancer in everyday clinical practice. Oral Oncol. 45, 440–446 (2009).
Chiyomaru, T., Enokida, H., Kawakami, K., Tatarano, S., Uchida, Y., Kawahara, K. et al. Functional role of LASP1 in cell viability and its regulation by microRNAs in bladder cancer. Urol. Oncol. (e-pub ahead of print 14 September 2010; PMID: 20843712).
Chiyomaru, T., Tatarano, S., Kawakami, K., Enokida, H., Yoshino, H., Nohata, N. et al. SWAP70, actin-binding protein, function as an oncogene targeting tumor-suppressive miR-145 in prostate cancer. Prostate (e-pub ahead of print 25 February 2011; PMID: 21360565).
Fuse, M., Nohata, N., Kojima, S., Sakamoto, S., Chiyomaru, T., Kawakami, K. et al. Restoration of miR-145 expression suppresses cell proliferation, migration and invasion in prostate cancer by targeting FSCN1. Int. J. Oncol. 38, 1093–1101 (2011).
Zhang, B., Liu, X. X., He, J. R., Zhou, C. X., Guo, M., He, M. et al. Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis 32, 2–9 (2011).
Su, Z. Z., Kang, D. C., Chen, Y., Pekarskaya, O., Chao, W., Volsky, D. J. et al. Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21, 3592–3602 (2002).
Warr, T., Ward, S., Burrows, J., Harding, B., Wilkins, P., Harkness, W. et al. Identification of extensive genomic loss and gain by comparative genomic hybridisation in malignant astrocytoma in children and young adults. Genes Chromosomes Cancer 31, 15–22 (2001).
Lee, S. G., Jeon, H. Y., Su, Z. Z., Richards, J. E., Vozhilla, N., Sarkar, D. et al. Astrocyte elevated gene-1 contributes to the pathogenesis of neuroblastoma. Oncogene 28, 2476–2484 (2009).
Yu, C., Chen, K., Zheng, H., Guo, X., Jia, W., Li, M. et al. Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30, 894–901 (2009).
Hu, G., Chong, R. A., Yang, Q., Wei, Y., Blanco, M. A., Li, F. et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell 15, 9–20 (2009).
Kikuno, N., Shiina, H., Urakami, S., Kawamoto, K., Hirata, H., Tanaka, Y. et al. Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26, 7647–7655 (2007).
Yoo, B. K., Emdad, L., Su, Z. Z., Villanueva, A., Chiang, D. Y., Mukhopadhyay, N. D. et al. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J. Clin. Invest. 119, 465–477 (2009).
Lee, S. G., Su, Z. Z., Emdad, L., Sarkar, D., Franke, T. F. & Fisher, P. B. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene 27, 1114–1121 (2008).
Sarkar, D., Park, E. S., Emdad, L., Lee, S. G., Su, Z. Z. & Fisher, P. B. Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res. 68, 1478–1484 (2008).
Acknowledgements
This study was supported by KAKENHI (C), 21592187.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Nohata, N., Hanazawa, T., Kikkawa, N. et al. Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC). J Hum Genet 56, 595–601 (2011). https://doi.org/10.1038/jhg.2011.66
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2011.66
Keywords
This article is cited by
-
Linc00239 Promotes Colorectal Cancer Development via MicroRNA-182-5p/Metadherin Axis
Biochemical Genetics (2024)
-
Circular RNA circZFR Promotes Hepatocellular Carcinoma Progression by Regulating miR-375/HMGA2 Axis
Digestive Diseases and Sciences (2021)
-
mPGES-1/PGE2 promotes the growth of T-ALL cells in vitro and in vivo by regulating the expression of MTDH via the EP3/cAMP/PKA/CREB pathway
Cell Death & Disease (2020)
-
The microRNA signatures: aberrantly expressed miRNAs in prostate cancer
Clinical and Translational Oncology (2019)
-
Comprehensive analysis of competitive endogenous RNAs network associated with head and neck squamous cell carcinoma
Scientific Reports (2018)
