[Show abstract][Hide abstract] ABSTRACT: Analysis of the microRNA (miRNA) expression signature of lung squamous cell carcinoma (lung-SCC) revealed that the expression levels of miR-133a were significantly reduced in cancer tissues compared with normal tissues. In this study, we focused on the functional significance of miR-133a in cancer cell lines derived from lung-SCC and the identification of miR-133a-regulated novel cancer networks in lung-SCC. Restoration of miR-133a expression in PC10 and H157 cell lines resulted in significant inhibition of cell proliferation, suggesting that miR-133a functions as a tumor suppressor. We used genome-wide gene expression analysis to identify the molecular targets of miR-133a regulation. Gene expression data and web-based searching revealed several candidate genes, including transgelin 2 (TAGLN2), actin-related protein2/3 complex, subunit 5, 16kDa (ARPC5), LAG1 homolog, ceramide synthase 2 (LASS2) and glutathione S-transferase pi 1 (GSTP1). ARPC5 and GSTP1 likely represent bona fide targets as their expression is elevated in lung-SCC clinical specimens. Furthermore, transient transfection of miR-133a, repressed ARPC5 and GSTP1 mRNA and protein levels. As cell proliferation was significantly inhibited in lung-SCC cells following RNAi knock down of either gene, ARPC5 and GSTP1 may function as oncogenes in the development of lung-SCC. The identification of a tumor suppressive miRNA and the novel cancer pathways it regulates could provide new insights into potential molecular mechanisms of lung-SCC carcinogenesis.
Journal of Human Genetics 11/2011; 57(1):38-45. DOI:10.1038/jhg.2011.126 · 2.46 Impact Factor
[Show abstract][Hide abstract] 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.
Journal of Human Genetics 08/2011; 56(8):595-601. DOI:10.1038/jhg.2011.66 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The glutathione S-transferase P1 (GSTP1) protein plays several critical roles in both normal and neoplastic cells, including phase II xenobiotic metabolism, stress responses, signaling and apoptosis. Overexpression of GSTP1 has been observed in many types of cancer, including head and neck squamous cell carcinoma (HNSCC). However, the role of GSTP1 in HNSCC is not well understood. We investigated the role of GSTP1 in two HNSCC cell lines, HSC3 and SAS. Silencing of GSTP1 revealed that cancer cell proliferation was significantly decreased in both cell lines. In addition, the frequency of apoptotic cells increased following si-GSTP1 transfection of HSC3 and SAS cell lines. Growing evidence suggests that microRNAs (miRNAs) negatively regulate gene expression and can function as oncogenes or tumor suppressors in human cancer. Based on the results of web-based searches, miR-133α is a candidate miRNA targeting GSTP1. Down-regulation of miR-133α has been reported in many types of human cancer, including HNSCC. Transient transfection of miR-133α repressed the expression of GSTP1 at both the mRNA and protein levels. The signal from a luciferase reporter was significantly decreased at one miR-133α target site at the 3'UTR of GSTP1, suggesting that miR-133α directly regulates GSTP1. Our data indicate that GSTP1 may have an oncogenic function and may be regulated by miR-133α, a tumor suppressive miRNA in HNSCC. The identification of a novel oncogenic pathway could provide new insights into potential mechanisms of HNSCC carcinogenesis.
International Journal of Molecular Medicine 03/2011; 27(3):345-52. DOI:10.3892/ijmm.2010.589 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides that can function as oncogenes or tumor suppressors in human cancer. Down-regulation of the miRNA miR-133a in many type of cancers, and a reduction of cell proliferation, migration, and invasion upon over-expression, suggests that miR-133a is a tumor suppressor. In this study, genome-wide gene expression analysis of HNSCC cells that over-express miR-133a showed that caveolin-1 (CAV1), a multifunctional scaffolding protein, is down-regulated, a result that was confirmed by real-time PCR and Western blot analysis. A luciferase reporter assay revealed that miR-133a is directly bound to CAV1 mRNA. Cancer cell migration and invasion were significantly inhibited in HNSCC cells transfected with si-CAV1. Therefore, CAV1 functions as an oncogene in HNSCC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into potential mechanism of HNSCC carcinogenesis.
International Journal of Oncology 01/2011; 38(1):209-17. DOI:10.3892/ijo-00000840 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are abundant classes of small non-coding RNAs of about 19-21 nucleotides in length, which regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. Recently, we identified a subset of down-regulated miRNAs (miR-145, miR-133a and miR-133b) in various cancer signatures. In this study, we elucidate the tumor suppressive functions of miR-145, miR-133a and miR-133b and identify their target genes in head and neck squamous cell carcinoma (HNSCC). These findings may provide new insight into the potential mechanisms of HNSCC carcinogenesis.
Japanese Journal of Head and Neck Cancer 05/2010; 36(1):1-8. DOI:10.5981/jjhnc.36.1