Dataset Information

HNRNPA2B1, as a m⁶A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.

ABSTRACT: N6-methyladenosine (m⁶A) modification is the most prevalent modification on eukaryotic RNA, and the m⁶A modification regulators were involved in the progression of various cancers. However, the functions of m⁶A regulators in oral squamous cell carcinoma (OSCC) remain poorly understood. In this study, we demonstrated that 13 of 19 m⁶A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19 m⁶A regulatory genes in OSCC. Moreover, HNRNPA2B1 expression is elevated in OSCC, and a high level of HNRNPA2B1 is significantly associated with poor overall survival in OSCC patients. Functional studies, combined with further analysis of the correlation between the expression of HNRNPA2B1 and the EMT-related markers from the TCGA database, reveal that silencing HNRNPA2B1 suppresses the proliferation, migration, and invasion of OSCC via EMT. Collectively, our work shows that HNRNPA2B1 may have the potential to promote carcinogenesis of OSCC by targeting EMT via the LINE-1/TGF-β1/Smad2/Slug signaling pathway and provide insight into the critical roles of HNRNPA2B1 in OSCC.

SUBMITTER: Zhu F

PROVIDER: S-EPMC8494978 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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HNRNPA2B1, as a m6A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.

Zhu Feiya F Yang Tianru T Yao Mianfeng M Shen Ting T Fang Changyun C

Frontiers in oncology 20210923

N6-methyladenosine (m6A) modification is the most prevalent modification on eukaryotic RNA, and the m6A modification regulators were involved in the progression of various cancers. However, the functions of m6A regulators in oral squamous cell carcinoma (OSCC) remain poorly understood. In this study, we demonstrated that 13 of 19 m6A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19 m<su ...[more]

PMID: 34631545

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Project description:Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck worldwide. Dysbiosis of the microbiome has increasingly been linked to the development of different kinds of cancer. Applying 16S rRNA gene sequence analysis and metatranscriptomic analyses, we characterized the longitudinal changes in the profiles and the function of the oral microbiome in a 4-nitroquinoline-1-oxide (4-NQO)-induced model of OSCC in gnotobiotic mice. We characterized the dynamics of the oral microbiome in this model using two different microbiome inocula: one from healthy mice and the other from mice bearing a 4-NQO-induced tumor. Mice colonized with different oral microbiomes and exposed to 4-NQO had increased tumor numbers and sizes compared to controls exposed to 4-NQO but lacking a microbiome. We observed an overall increase in diversity in the tumorigenic samples compared to that in the nontumor group not exposed to 4-NQO. Despite the variability in community dynamics, specific patterns emerged during the progression of the disease. In the two groups that were inoculated with the OSCC-associated microbiome, we observed opposite profiles of abundance in Parabacteroides and Corynebacterium While the percentage of Parabacteroides bacteria decreased in the control group, it increased in the OSCC group, and the opposite was observed for Corynebacterium The metatranscriptomic analysis revealed overexpression of the same metabolic signatures associated with OSCC regardless of the community profile. These included nitrogen transport, response to stress, interspecies interactions, Wnt pathway modulation, and amino acid and lipid biosynthesis. Thus, these results seem to suggest that certain collective physiological activities are critical for microbiome-mediated OSCC progression.IMPORTANCE There is growing evidence that changes in the microbiome are associated with carcinogenesis. To date, no consistent oral microbiome composition associated with OSCC has been identified. Longitudinal and functional studies like the study presented here should yield a better understanding of the role that the oral microbiome plays in OSCC. Our findings, obtained using a germ-free mouse model, indicate that the presence of different oral microbiomes enhances tumorigenesis and increases the final number of tumors in mice. By studying community-wide expression profiles, we found that regardless of the phylogenetic composition of the microbiome, the same metabolic activities were consistently associated with OSCC. Therefore, due to the functional redundancy of the microbiome, the critical element in explaining the contribution of the microbiota in OSCC is the collective physiological activity of the community, thus accounting for the previous inability to identify a consensus community profile or etiologic agents for OSCC.

Project description:Oral squamous cell carcinoma (OSCC) is the most frequent type of oral malignancy with high metastasis and poor prognosis. The deubiquitinating enzyme Ubiquitin Specific Peptidase 44 (USP44) regulates the mitotic checkpoint, and its deficiency leads to aneuploidy and increases tumor incidence. However, the role of USP44 in OSCC is not well understood. Herein, we analyzed mRNA sequencing data of OSCC samples downloaded from the TCGA and GEO databases and found that USP44 was decreased in human OSCC tissues and was positively correlated to the survival of OSCC patients. To investigate the biological impact of USP44, we used recombinant lentiviruses to overexpress or knockdown USP44 expression in OSCC cell lines, which were also injected subcutaneously or into the lateral tail vein of Male BALB/c nude mice to model tumorigenesis or lung metastasis in vivo, respectively. The results showed that overexpression of USP44 inhibited malignant cell phenotypes in vitro and suppressed tumor growth and lung metastasis in vivo, while its downregulation had the opposite effects. Comprehensive proteomic analyses through Co-IP mass spectrometry and label-free quantitative LC-MS/MS methods identified 112 differentially expressed proteins positively regulated by USP44, among which 13 were involved in cancer-related pathways including apoptotic signaling and cell cycle regulation. PPI analysis identified Hexamethylene Bis-Acetamide-Inducible Protein 1 (HEXIM1) as the hub protein. Upregulation of USP44 enhanced HEXIM1 protein stability, leading to its higher expression in OSCC cells. Silencing of HEXIM1 further enhanced the malignant phenotype of OSCC cells. At the same time, HEXIM1 knockdown reversed the antitumor effects of USP44. These findings demonstrated that USP44 acted as a critical tumor suppressor in OSCC by inhibiting cell proliferation and metastasis through the stabilization of HEXIM1 protein, suggesting that USP44-HEXIM1 axis is a promising target for OSCC therapy.

Dataset Information

HNRNPA2B1, as a m⁶A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.

Publications

HNRNPA2B1, as a m<sup>6</sup>A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.

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