Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC)

Nohata, Nijiro; Hanazawa, Toyoyuki; Kikkawa, Naoko; Mutallip, Muradil; Sakurai, Daiju; Fujimura, Lisa; Kawakami, Kazumori; Chiyomaru, Takeshi; Yoshino, Hirofumi; Enokida, Hideki; Nakagawa, Masayuki; Okamoto, Yoshitaka; Seki, Naohiko

doi:10.1038/jhg.2011.66

Cited by 108 publications

(84 citation statements)

References 38 publications

(66 reference statements)

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“…16,17,[23][24][25][26][27][28][29][30][31][39][40][41][42] Downregulation of miR-375 has been reported for gastric cancer, cervical cancer, pancreatic ductal adenocarcinoma and hepatocellular carcinoma. 26,27,29,30,[43][44][45] In gastric cancer, ectopic expression of miR-375 in cancer cells reduced cell viability and induced apoptosis by targeting PDK1 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein z (YWHAZ).…”

Section: Aberrant Expression Of Mir-375 and Its Target Genes In Othermentioning

confidence: 99%

“…The restoration of miR-375 caused significant inhibition of cell proliferation and induction of cell apoptosis in SAS and FaDu cell lines derived from HNSCC. 16 In maxillary sinus SCC, restoration of miR-375 also inhibited cell proliferation and invasion in IMC-3 cells. 17 Similarly, another group demonstrated that transfection of miR-375 into FaDu, UTSCC-8 and UTSCC-42a cell lines reduced proliferation and clonogenicity.…”

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

“…Our data revealed that the metadherin (MTDH) and lactate dehydrogenase B were direct targets of miR-375 in HNSCC and maxillary sinus SCC. 16,17 Silencing of the MTDH gene caused significant inhibition of cancer cell proliferation, suggesting MTDH functions as an oncogene in HNSCC. 16 Very interestingly, another group also reported that MTDH was regulated by miR-375 and that both miR-375 overexpression and MTDH knockdown in HNSCC cell lines resulted in significant decreases in tumor formation in SCID mice.…”

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

“…16,17 Silencing of the MTDH gene caused significant inhibition of cancer cell proliferation, suggesting MTDH functions as an oncogene in HNSCC. 16 Very interestingly, another group also reported that MTDH was regulated by miR-375 and that both miR-375 overexpression and MTDH knockdown in HNSCC cell lines resulted in significant decreases in tumor formation in SCID mice. 24 In ESCC, expression signatures revealed that miR-375 was significantly reduced in cancer cells.…”

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

“…11-15 Our previous studies of HNSCC and ESCC signatures found that miR-375 was significantly reduced in cancer tissues 13,15 and functioned as a tumor suppressor. 16,17 Other research groups also showed downregulation of miR-375 in HNSCC and ESCC and other types of human cancers. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] In this review, we focus on HNSCC and ESCC and describe the aberrant expression of miRNAs in these cancers and the cancer pathways they may regulate in these diseases.…”

Section: Introductionmentioning

confidence: 99%

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The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

et al. 2012

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MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation. In cancer research, a growing body of evidence has indicated that miRNAs are aberrantly expressed in many types of human cancers and can function either as tumor suppressors or oncogenes. Bioinformatic predictions suggest that miRNAs regulate more than 30% of protein-coding genes. Aberrant expression of miRNAs in cancer cells causes destruction of miRNA-regulated messenger RNA networks. Therefore, the identification of miRNA-regulated cancer pathways is important for understanding the molecular mechanisms of human cancer. Searching for the aberrant expression of miRNAs in cancer cells is the first step in the functional analysis of miRNAs in cancer cells. Genome-wide miRNA expression signatures can rapidly and precisely reveal aberrant expression of miRNA in cancers. The miRNA expression signatures of human cancers have revealed that miR-375 is significantly downregulated in cancer cells. Our recent data on maxillary sinus, hypopharyngeal and esophageal squamous cell carcinomas have suggested that miR-375 is frequently downregulated and functions as a tumor suppressor that targets several oncogenic genes in cancer cells. In this review, we focus on several types of human squamous cell carcinoma and describe the aberrant expression of miRNAs and the cancer pathways they regulate in these diseases.

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Section: Aberrant Expression Of Mir-375 and Its Target Genes In Othermentioning

confidence: 99%

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

Section: Aberrant Expression and Functional Significance Of Mir-375 Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

et al. 2012

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Focal aberrations indicate EYA2 and hsa‐miR‐375 as oncogene and tumor suppressor in cervical carcinogenesis

Bierkens

Krijgsman

Wilting

et al. 2012

Genes Chromosomes & Cancer

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Cervical cancer results from persistent infection with high-risk human papillomavirus (hrHPV). Common genetic aberrations in cervical (pre)cancers encompass large genomic regions with numerous genes, hampering identification of driver genes. This study aimed to identify genes functionally involved in HPV-mediated transformation by analysis of focal aberrations (<3 Mb) in high-grade cervical intraepithelial neoplasia (hgCIN). Focal chromosomal aberrations were determined in high-resolution array comparative genomic hybridization data of 60 hgCIN. Genes located within focal aberrations were validated using 2 external gene expression datasets or qRT-PCR. Functional roles of candidate genes EYA2 (20q13) and hsa-miR-375 (2q35) were studied by siRNA-mediated knock-down and overexpression, respectively, in hrHPV-containing cell lines. We identified 74 focal aberrations encoding 305 genes. Concurrent altered expression in hgCIN and/or cervical carcinomas compared with normal cervical samples was shown for ATP13A3, HES1, OPA1, HRASLS, EYA2, ZMYND8, APOBEC2, and NCR2. Gene silencing of EYA2 significantly reduced viability, migratory capacity, and anchorage-independent growth of HPV16-transformed keratinocytes. For hsa-miR-375, a direct correlation between a (focal) loss and significantly reduced expression was found. Downregulation of hsa-miR-375 expression was confirmed in an independent series of cervical tissues. Ectopic expression of hsa-miR-375 in 2 cervical carcinoma cell lines reduced cellular viability. Our data provide a proof of concept that chromosomal aberrations are actively contributing to HPV-induced carcinogenesis and identify EYA2 and hsa-miR-375 as oncogene and tumor suppressor gene, respectively.

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The emerging role of miR‐375 in cancer

Yan

Lin

2013

Intl Journal of Cancer

209

176

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MicroRNAs (miRNAs) are evolutionarily conserved, small noncoding RNAs that are believed to play fundamental roles in various biological processes through regulation of gene expression at the level of posttranscription. MiR-375 was first identified as a pancreatic islet-specific miRNA regulating insulin secretion. However, further study revealed that miR-375 is a multifunctional miRNA participating in pancreatic islet development, glucose homeostasis, mucosal immunity, lung surfactant secretion and more importantly, tumorigenesis. Recently, miR-375 has been found significantly downregulated in multiple types of cancer, and suppresses core hallmarks of cancer by targeting several important oncogenes like AEG-1, YAP1, IGF1R and PDK1. The alteration of miR-375 in cancer is caused by a variety of mechanisms, including the dysregulation of transcription factors, aberrant promoter methylation and so on. Reduced expression of miR-375 in tissue or circulation may indicate the presence of neoplasia as well as a poor prognosis of many malignant cancers. Moreover, miR-375 stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of miR-375 in cancer progression; the mechanisms underlying the dysregulation of miR-375; the potential use of miR-375 in prognosis and diagnosis and the therapeutic prospects of miR-375 in cancer.MicroRNAs (miRNAs) are small approximately 22 nucleotide single stranded noncoding RNAs. The biosynthesis of miRNAs is involved in miRNA gene transcription by RNA polymerase II (Pol II) and ribonuclease III (RNase III) processing within and outside the nucleus by Drosha and Dicer, respectively.

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Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC)

Cited by 108 publications

References 38 publications

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways

Focal aberrations indicate EYA2 and hsa‐miR‐375 as oncogene and tumor suppressor in cervical carcinogenesis

The emerging role of miR‐375 in cancer

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