HNRNPA2B1, as a m6A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Zhu F
PROVIDER: S-EPMC8494978 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N6-methyladenosine (m6A) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the m6A modification in the 3' UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with m6A reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 m6A methylation, suggesting that the METTL3-m6A-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.
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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.
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Project description:BACKGROUND:Inflammasomes are reported to be abnormally expressed and activated in several malignancies and play important roles in tumor development. The present study was designed to investigate the expression and function of the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome in oral squamous cell carcinoma (OSCC). METHODS:NLRP3 expression in OSCC cell lines and the normal human immortalized oral epithelial cells (HIOEC) was determined by real-time PCR and western blot. Immunohistochemistry was used to examine the expression of NLRP3 and IL-1β in the paraffin-embedded OSCC tissues. The proliferation of OSCC cells was detected by the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and cell colony formation ability of the OSCC cells was also evaluated. Tumor cell migration or invasion was measured by the transwell assay and related protein markers were determined by western blot. A mouse xenograft model was established to investigate the OSCC tumor growth in vivo. RESULTS:Significant higher expression of NLRP3 was observed in the OSCC cells. Obvious expression of NLRP3 and IL-1β was found in the paraffin-embedded OSCC tissues, and the NLRP3 expression levels were correlated with the tumor size, lymphonode metastatic status and IL-1β expression. Downregulating NLRP3 expression markedly reduced the cleavage of caspase-1 and production of IL-1β in OSCC cells. NLRP3 knockdown also inhibited the proliferation, migration and invasion of OSCC cells. Further investigation indicated that expressions of E-cadherin and vimentin in OSCC cells were increased, while N-cadherin expression was decreased after NLRP3 knockdown. Downregulating NLRP3 expression in OSCC cells significantly reduced the tumor growth in vivo. CONCLUSIONS:Our data suggested that the increased expression of NLRP3 in OSCC was associated with tumor growth and metastasis. NLRP3 may be considered as a potential target for OSCC therapy.
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Project description:Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide, and with 354 864 new cases each year. Cancer metastasis, recurrence, and drug resistance are the main causes to cripples and deaths of OSCC patients. As potent growth factors, fibroblast growth factors (FGFs) are frequently susceptible to being hijacked by cancer cells. In this study, we show that FGF8 is upregulated in OSCC tissues and high FGF8 expression is related with a set of clinicopathologic parameters, including age, drinking, and survival time. FGF8 treatment enhances the invasive capability of OSCC cells. Lentivirus-based FGF8 expression promotes OSCC metastasis in a mouse lung metastasis model. Further, mechanistic study demonstrates that FGF8 induces epithelial-mesenchymal transition (EMT) in OSCC cells. These results highlight a pro-metastatic function of FGF8, and underscore the role of FGF8 in OSCC development.
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Project description:PTP4A1 (Protein tyrosine phosphatase 4A1) is a protein tyrosine phosphatase that regulates a range of pro-oncogenic signaling pathways. Here, we report a novel role for PTP4A1 in oral squamous cell carcinoma (OSCC) growth and development. We show that PTP4A1 is frequently overexpressed in OSCC cells and tissues compared to adjacent non-tumor tissue. In OSCC, the overexpression of PTP4A1 increased cell growth and invasion in vitro, and enhanced tumor progression in vivo. At the molecular level, PTP4A1 was found to regulate mitochondrial metabolic reprogramming to enhance the invasive capacity of OSCC cells. Mechanistically, these effects were mediated through binding to pyruvate kinase isoenzyme M2 (PKM2) to promote its expression and aconitase 2 (ACO2) to enhance its degradation. Together, these data reveal PTP4A1 as a viable target for OSCC therapeutics.
| S-EPMC10541904 | biostudies-literature
Project description:Oral squamous cell carcinoma (OSCC) represents 95% of oral malignancies and invasion, and metastasis underlies disease morbidity and mortality. We recently established a direct link between oral inflammation and cancer invasion by showing that neutrophils increase OSCC invasion through a tumor necrosis factor (TNFα)-dependent mechanism. The objective of this study was to characterize OSCC-associated inflammation and to determine the molecular mechanisms underlying inflammation-mediated OSCC invasion. Our results showed a significant increase in neutrophil infiltration, the neutrophil-to-lymphocyte ratio in the OSCC microenvironment and increased inflammatory markers, particularly TNFα in saliva. We performed next-generation sequencing of the TNFα-treated OSCC cells and showed marked overexpression of over 180 genes distributed among clusters related to neutrophil recruitment, invasion, and invadopodia. At the molecular level, TNFα treatment increased phosphoinositide 3-kinase (PI3K)-mediated invadopodia formation and matrix metalloproteinase (MMP)-dependent invasion. We show here that TNFα promotes a pro-inflammatory and pro-invasion phenotype leading to the recruitment and activation of inflammatory cells in a paracrine mechanism. Increased TNFα in the tumor microenvironment tips the balance towards invasion leading to decreased overall survival and disease-free survival. This represents a significant advancement of oral cancer research and will support new treatment approaches to control OSCC invasion and metastasis.
| S-EPMC6044370 | biostudies-literature
Project description:BackgroundEpigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.Results429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.ConclusionsHistone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.
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Project description:N6-methyladenosine (m6A) modification is the most abundant modification on eukaryotic RNA. In recent years, lots of studies have reported that m6A modification and m6A RNA methylation regulators were involved in cancer progression. However, the m6A level and its regulators in esophageal cancer (ESCA) remain poorly understood. In this study, we analyzed the expression of m6A regulators using The Cancer Genome Atlas data and found 14 of 19 m6A regulators are significantly increased in ESCA samples. Then we performed a univariate Cox regression analysis and LASSO (least absolute shrinkage and selection operator) Cox regression model to investigate the prognostic role of m6A regulators in ESCA, and the results indicated that a two-gene prognostic signature including ALKBH5 and HNRNPA2B1 could predict overall survival of ESCA patients. Moreover, HNRNPA2B1 is higher expressed in high-risk scores subtype of ESCA, indicating that HNRNPA2B1 may be involved in ESCA development. Subsequently, we confirmed that the level of m6A and HNRNPA2B1 was significantly increased in ESCA. We also found that HNRNPA2B1 expression positively correlated with tumor diameter and lymphatic metastasis of ESCA. Moreover, functional study showed that knockdown of HNRNPA2B1 inhibited the proliferation, migration, and invasion of ESCA. Mechanistically, we found that knockdown of HNRNPA2B1 inhibited the expression of de novo fatty acid synthetic enzymes, ACLY and ACC1, and subsequently suppressed cellular lipid accumulation. In conclusion, our study provides critical clues to understand the role of m6A and its regulators in ESCA. Moreover, HNRNPA2B1 functions as an oncogenic factor in promoting ESCA progression via up-regulation of fatty acid synthesis enzymes ACLY and ACC1, and it may be a promising prognostic biomarker and therapeutic target for human ESCA.
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Project description:BACKGROUND:Increasing studies have demonstrated that long non-coding RNAs (lncRNAs) play an important role in tumor progression. However, the potential biological functions and clinical importance of Linc01234 in oral squamous cell carcinoma (OSCC) remain unclear. METHODS:We evaluated the expression profile and prognostic value of Linc01234 in OSCC tissues by RT-qPCR. Then, functional in vitro experiments were performed to investigate the effects of Linc01234 on tumor growth, migration and invasion in OSCC. Mechanistically, RT-qPCR, bioinformatic analysis and dual luciferase reporter assays were performed to identify a competitive endogenous RNA (ceRNA) mechanism involving Linc01234, miR-433-3p and PAK4. RESULTS:We found that Linc01234 was clearly upregulated in OSCC tissues and cell lines, and its level was positively associated with T stage, lymph node metastasis, differentiation and poor prognosis of patients with OSCC. Our results shown that Linc01234 inhibited cell proliferation and metastatic abilities in CAL27 and SCC25 cells following its knockdown. Mechanistic analysis indicated that Linc01234 may act as a ceRNA (competing endogenous RNA) of miR-433-3p to relieve the repressive effect of miR-433-3p on its target PAK4. CONCLUSIONS:Our results indicated that Linc01234 promotes OSCC progression through the Linc01234/miR-433/PAK4 axis and might be a potential therapeutic target for OSCC.
| S-EPMC7011552 | biostudies-literature
Project description:Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.
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