Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas

Minor, Jacob; Wang, Xiaotian; Zhang, Fang; Song, John I.; Jimeno, Antonio; Wang, Xiao Jing; Lu, Xian; Gross, Neil D.; Kulesz‐Martin, Molly; Wang, Daren; Lu, Shi

doi:10.1016/j.oraloncology.2011.11.006

Cited by 86 publications

(70 citation statements)

References 28 publications

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“…In normal head and neck tissue, miR-9-positive cells were undetectable ( Figure 6A), however in head and neck SCCs, 13 of 64 samples (21%; Table 1) contained sporadic miR-9-positive cells (not shown). This low incidence of miR-9-positive tumors is consistent with the recent finding that miR-9 is often methylated in SCCs (44). In contrast, however, 67% (50 of 75) of SCC lymph node metastatic lesions contained miR-9-positive cells ( Figure 6A and Table 1).…”

Section: K15kras G12d Smad4 -/-Sccs Retained Csc Populations But Msupporting

confidence: 90%

“…miR-9-positive cell numbers are increased in metastatic human primary SCCs and SCC metastases. It has been reported that miR-9 is frequently methylated in human cancers, including SCCs, and as such, miR-9 has been suggested to be a tumor suppressor (42)(43)(44). The effect of miR-9 on the metastatic behavior of SCCs observed in our animal model and in the human SCC cell lines prompted us to examine whether miR-9 was elevated in human SCCs.…”

Section: K15kras G12d Smad4 -/-Sccs Retained Csc Populations But Mmentioning

confidence: 82%

“…The finding that miR-9 was overexpressed in metastatic K15.Kras G12D .Smad4 -/-SCCs was initially a surprise to us, since miR-9 is often methylated in human tumors, including SCCs (44,59). However, miR-9 has been shown to be overexpressed in certain metastatic cancer types (41,49).…”

Section: Methodsmentioning

confidence: 99%

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Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

et al. 2013

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Squamous cell carcinomas (SCCs) originate in stratified epithelia, with a small subset becoming metastatic. Epithelial stem cells are targets for driver mutations that give rise to SCCs, but it is unknown whether they contribute to oncogenic multipotency and metastasis. We developed a mouse model of SCC by targeting two frequent genetic mutations in human SCCs, oncogene Kras G12D activation and Smad4 deletion, to mouse keratin 15-expressing (K15 + ) stem cells. We show that transgenic mice developed multilineage tumors, including metastatic SCCs. Among cancer stem cell-enriched (CSC-enriched) populations, those with increased side population (SP) cells correlated with epithelial-mesenchymal transition (EMT) and lung metastasis. We show that microRNA-9 (miR-9) contributed to SP expansion and metastasis, and miR-9 inhibition reduced the number of SP cells and metastasis. Increased miR-9 was detected in metastatic human primary SCCs and SCC metastases, and miR-9-transduced human SCC cells exhibited increased invasion. We identified α-catenin as a predominant miR-9 target. Increased miR-9 in human SCC metastases correlated with α-catenin loss but not E-cadherin loss. Our results demonstrate that stem cells with Kras G12D activation and Smad4 depletion can produce tumors that are multipotent and susceptible to EMT and metastasis. Additionally, tumor initiation and metastatic properties of CSCs can be uncoupled, with miR-9 regulating the expansion of metastatic CSCs. IntroductionSquamous cell carcinomas (SCCs) are derived from stratified epithelia present within the skin and oral cavity. A subset of aggressive SCCs become metastatic and lead to metastasis-associated death. The rate of metastasis in skin SCCs ranges from 0.1% to 10% (1), with poorly differentiated tumors and those with greater vertical tumor thickness having an increased risk of metastasis (2). Genetic alterations and intrinsic tumor cell properties controlling SCC metastasis are largely unknown. Genetically engineered mice provide a powerful tool for dissecting driver mutations that contribute to SCC initiation and metastasis. To date, very few genetic mutations causing spontaneous SCC formation and metastasis have been found, particularly metastasis to the lung, which is the leading cause of SCC-associated death (3). Mice with a Smad4 deletion in stratified epithelia develop spontaneous SCCs in the skin, oral cavity, and forestomach (4-6). Among these models, oral SCCs metastasize to lymph nodes (4), whereas skin and forestomach SCCs do not metastasize (5, 6).Because stratified epithelia undergo constant self-renewal and rapid turnover, it is believed that driver mutations for SCCs must initially occur in resident stem cells that renew these epithelia throughout life. In mouse skin, the hair follicle bulge harbors

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Section: K15kras G12d Smad4 -/-Sccs Retained Csc Populations But Msupporting

confidence: 90%

Section: K15kras G12d Smad4 -/-Sccs Retained Csc Populations But Mmentioning

confidence: 82%

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Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

et al. 2013

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“…Reduced miR-9 expression was associated with the methylation of miR-9 in tumor tissues. The methylations of miR-9-1 and miR-9-3 are sensitive and specific biomarkers for HNSCC, particularly for oral and oropharyngeal squamous cell carcinomas (39). The mechanisms for the downregulation of miR-99a in OSCC remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA 99a in oral squamous cell carcinomas contributes to the growth and survival of oral cancer cells

Yan

Lai

et al. 2012

Mol Med Report

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Abstract. microRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by either translational inhibition or mRNA degradation. miRNAs play pivotal roles in physiological functioning and pathological progression. The function of microRNA-99a (miR-99a) in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, we investigated the roles of miR-99a in OSCC development and the underlying mechanisms in 25 cases of primary OSCC tissues and Tca-8113 cells. The cells were analyzed using FACS analysis and western blotting. Results showed that the expression levels of miR-99a were markedly decreased in OSCC tissues compared with the adjacent non-tumor tissues (n=25). The results of in vitro experiments showed that miR-99a mimics significantly inhibited the proliferation of Tca-8113 cells, a tongue squamous carcinoma cell line, and that miR-99a mimics markedly induced the apoptosis of Tca-8113 cells. Furthermore, we demonstrated that mammalian target of rapamycin (mTOR) was directly targeted by miR-99a, as the overexpression of miR-99a in Tca-8113 cells downregulated the protein expression level of mTOR. Thus, our findings suggest that the downregulation of miR-99a in OSCC tissues is associated with tumor development. miR-99a regulates the growth and survival of OSCC cells and may be exploited as a biomarker and therapeutic target for patients with OSCC.

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“…miR-9 down-regulation is considered a poor survival marker in cervical cancer (15), lung squamous cell carcinoma (17), and in acute lymphoblastic leukemia (21), and it was associated with development of cancer metastasis (19,(22)(23)(24). Silencing of miR-9 by cytosine-phosphate-guanine (CpG) island hypermethylation was found in many tumors (16,17,(21)(22)(23)25), clearly indicating that miR-9 possesses tumor suppressor features. However, the molecular mechanism leading to miR-9 silencing in cancer has not been defined.…”

mentioning

confidence: 99%

Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis

Senyuk

Zhang

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNA-9 (miR-9) is emerging as a critical regulator of organ development and neurogenesis. It is also deregulated in several types of solid tumors; however, its role in hematopoiesis and leukemogenesis is not yet known. Here we show that miR-9 is detected in hematopoietic stem cells and hematopoietic progenitor cells, and that its expression increases during hematopoietic differentiation. Ectopic expression of miR-9 strongly accelerates terminal myelopoiesis and promotes apoptosis in vitro and in vivo. Conversely, in hematopoietic progenitor cells, the inhibition of miR-9 with a miRNA sponge blocks myelopoiesis. Ecotropic viral integration site 1 (EVI1), required for normal embryogenesis, is considered an oncogene because its inappropriate up-regulation induces malignant transformation in solid and hematopoietic cancers. Here we show that EVI1 binds to the promoter of miR-9-3, leading to DNA hypermethylation of the promoter and repression of miR-9. Moreover, miR-9 expression reverses a myeloid differentiation block that is induced by EVI1. Our findings indicate that EVI1, when inappropriately expressed, delays or blocks myeloid differentiation at least in part by DNA hypermethylation and down-regulation of miR-9. It was reported that Forkhead box class O genes (FoxOs) inhibit myeloid differentiation and prevent differentiation of leukemia-initiating cells. Here we identify both FoxO1 and FoxO3 as direct targets of miR-9 in hematopoietic cells and find that up-regulation of FoxO3 inhibits miR-9-induced myelopoiesis. These results reveal a unique role of miR-9 in myelopoiesis and in the pathogenesis of EVI1-induced myeloid neoplasms and provide insights into the epigenetic regulation of miR9 in tumorigenesis.

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Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas

Cited by 86 publications

References 28 publications

Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

Downregulation of microRNA 99a in oral squamous cell carcinomas contributes to the growth and survival of oral cancer cells

Critical role of miR-9 in myelopoiesis and EVI1-induced leukemogenesis

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