Oral Tumorigenesis Research Articles

Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation‐dependent transcription from chromatin templates in vitro. Acetylation of NPM1 by p300 has been shown to further enhance its transcription activation potential. Moreover, its total and acetylated pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP‐seq analyses, we provide the first genome‐wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co‐occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high‐throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II‐driven transcription and regulates the expression of genes that promote oral tumorigenesis.

Age-Related Cancer-Associated Microbiota Potentially Promotes Oral Squamous Cell Cancer Tumorigenesis by Distinct Mechanisms.

The oral squamous cell cancer (OSCC) incidence in young patients has increased since the end of the last century; however, the underlying mechanism is still unclear. Oral microbiota dysbiosis was proven to be a tumorigenesis factor, and we propose that there is a distinct bacterial composition in young patients that facilitates the progression of OSCC. Twenty elderly (>60 years old) and 20 young (<50 years old) subjects were included in this study. OSCC tissue was collected during surgery, sent for 16S rDNA sequencing and analyzed by the QIIME 2 pipeline. The results showed that Ralstonia, Prevotella, and Ochrobactrum were significantly enriched in younger OSCC tissue microbiota, while Pedobacter was more abundant in elderly OSCC tissues. Fusobacterium had high relative abundance in both cohorts. At the phylum level, Proteobacteria was the dominant taxon in all samples. The functional study showed that there were significant differences in the taxa abundance from metabolic and signaling pathways. The results indicated that the microbiota of younger OSCC tissues differed from that of elderly OSCC tissues by both taxon composition and function, which partially explains the distinct roles of bacteria during tumorigenesis in these two cohorts. These findings provide insights into different mechanisms of the microbiota-cancer relationship with regard to aging.

Linc-ROR genetic variants are associated with the advanced disease in oral squamous cell carcinoma

ObjectiveThe objective of this study is to identify the association between linc-ROR genetic variants and oral squamous cell carcinoma tumorigenesis. DesignFour genetic variants of linc-ROR (rs6420545, rs4801078, rs1942348, and rs9636089) were analyzed in 178 OSCCs and 191 controls of the South Indian population by PCR amplification followed by restriction digestion. In addition, we examined whether these variants alter linc-ROR expression levels and the progression of OSCC. ResultsThe frequency of linc-ROR rs6420545 and rs4801078 genotypes were significantly associated with advanced tumor grade (>2) (p = 0.002 and p = 0.048), and nodal metastasis (p = 0.001 and p = 0.019), respectively. We observed a significant association of rs6420545 specifically in the over-dominant model [OR 1.77 (95%CI; 1.17–2.68); p = 0.006] and rs9636089 in dominant model [OR 2.17 (95%CI; 1.06 – 4.46); p = 0.03], and allelic model [OR 2.26 (95%CI; 1.13 – 4.53) p = 0.02], respectively. Further, significant upregulation of linc-ROR (p = 0.005) was observed in our cohort, consistent with the HNSCC TCGA dataset (p < 0.0001). ConclusionsOur findings suggest that the linc-ROR genetic variants could contribute to the metastasis and progression mainly in the late event of tumorigenesis of OSCCs and these variants could be useful in the precision therapeutic management of this cancer particularly in prognosis.

Histone Chaperone Nucleophosmin Regulates Transcription of Key Genes Involved in Oral Tumorigenesis.

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. p300-mediated acetylation of NPM1 has been shown to further enhance its transcription activation potential. Acetylated and total NPM1 pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.

A dysbiotic microbiome promotes head and neck squamous cell carcinoma.

Recent studies have reported dysbiotic oral microbiota and tumor-resident bacteria in human head and neck squamous cell carcinoma (HNSCC). We aimed to identify and validate oral microbial signatures in treatment-naïve HNSCC patients compared with healthy control subjects. We confirm earlier reports that the relative abundances of Lactobacillus spp. and Neisseria spp. are elevated and diminished, respectively, in human HNSCC. In parallel, we examined the disease-modifying effects of microbiota in HNSCC, through both antibiotic depletion of microbiota in an induced HNSCC mouse model (4-Nitroquinoline 1-oxide, 4NQO) and reconstitution of tumor-associated microbiota in a germ-free orthotopic mouse model. We demonstrate that depletion of microbiota delays oral tumorigenesis, while microbiota transfer from mice with oral cancer accelerates tumorigenesis. Enrichment of Lactobacillus spp. was also observed in murine HNSCC, and activation of the aryl-hydrocarbon receptor was documented in both murine and human tumors. Together, our findings support the hypothesis that dysbiosis promotes HNSCC development.

Microbiome dysbiosis inhibits carcinogen-induced murine oral tumorigenesis.

Oral cancer is one of the most common cancers worldwide and ranks fourth for the mortality rate of cancers in males in Taiwan. The oral microbiota is the microbial community in the oral cavity, which is essential for maintaining oral health, but the relationship between oral tumorigenesis and the oral microbiota remains to be clarified. This study evaluated the effect of microbiome dysbiosis on oral carcinogenesis in mice, and the impact of the microbiome and its metabolic pathways on regulating oral carcinogenesis. We found that antibiotics treatment decreases carcinogen-induced oral epithelial malignant transformation. Microbiome analysis based on 16S rRNA gene sequencing revealed that the species richness of fecal specimens was significantly reduced in antibiotic-treated mice, while that in the salivary specimens was not decreased accordingly. Differences in bacterial composition, including Lactobacillus animalis abundance, in the salivary samples of cancer-bearing mice was dramatically decreased. L. animalis was the bacterial species that increased the most in the saliva of antibiotic-treated mice, suggesting that L. animalis may be negatively associated with oral carcinogenesis. In functional analysis, the microbiome in the saliva of the tumor-bearing group showed greater potential for polyamine biosynthesis. Immunochemical staining proved that spermine oxidase, an effective polyamine oxidase, was upregulated in mouse oral cancer lesions. In conclusion, oral microbiome dysbiosis may alter polyamine metabolic pathways and reduce carcinogen-induced malignant transformation of the oral epithelium.

Immunoexpression of Podoplanin in Leukoplakia and Oral Squamous Cell Carcinoma and its Correlation with Survival: A Research Protocol

Introduction: Podoplanin (PDPN) is a well-conserved mucintype transmembrane glycoprotein. According to various studies, podoplanin expression is seen in various human cancers and it also encourages the progression of the tumour. A high PDPN expression, specifically in oral cancers, shows a significant relation to the metastasis of lymph nodes and poor patient survival, suggesting its substantial role in identifying the malignant transformation of a lesion by its expression in initial oral tumourigenesis. Only few studies have mentioned the use of podoplanin marker in detection of malignant transformation of Oral Potentially Malignant Disorders (OPMDs). Most malignant transformations are seen in cases of oral leukoplakia. This study will help in early diagnosis of malignant transformation of leukoplakia by showing an increased expression of podoplanin thereby resulting in better treatment and prognosis of the disease. Aim: To evaluate immunoexpression of podoplanin in leukoplakia and oral squamous cell carcinoma and also to correlate it with the clinicopathological characteristics of leukoplakia and Oral Squamous Cell Carcinoma (OSCC) and the survival of OSCC patients. Materials and Methods: This retrospective study will be conducted in the Oral Pathology Department at Sharad Pawar Dental College, Wardha, Maharashtra, India. Surgically operated OSCC cases from year 2005-2019 in this Institute will be retrieved from the archival of the department. Ninety samples in total will be taken for the study which will be further divided into three groups, consisting of 30 samples in each group as follows: leukoplakia, OSCC and normal oral mucosa (control). Immunohistochemical staining will be carried out, and podoplanin (PDPN) immunoexpression with different clinical characteristics of leukoplakia and oral squamous cell carcinoma will be assessed. Broder's grading system will be used for histopathological grading of all cases of OSCC. The Chi-square test, Kaplan-Meier method, and the log-rank test will be used to statistically analyse the data.

Identification of Candidate Target Genes and Immune Cells in Oral Squamous Cell Carcinoma.

Background The advance of new treatment strategies for more effective management of oral cancer requires identification of novel biological targets. Therefore, the purpose of this study is to identify novel biomarkers associated with oral tumorigenesis and prognostic signature by comparing gene expression profile of oral squamous cell carcinomas (OSCCs). Methods Four datasets including GSE25099, GSE30784, GSE37991, and GSE41613 were collected from Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Cox model analysis, identification of key genes, and Kaplan-Meier analysis were also performed. The xCell was utilized to analyze the infiltration levels of immune cells. Results A total of 235 differentially expressed genes (DEGs) were found to be dysregulated in OSCC. These genes were mainly enriched in ECM receptor interaction and focal adhesion. Cox regression analysis identified 10 genes considered as key genes. Kaplan-Meier analysis showed that low expression of SERPINE1 (also known as PAI-1), high expression of CD1C, and C-X3-C motif chemokine receptor 1 (CX3CR1) were associated with well prognostic status in OSCC patients. In addition, we constructed a 3-immune-cell signature (myeloid dendritic cell, T cell CD4+ central memory, and common myeloid progenitor) that may be used to predict the survival status of OSCC patients. Conclusion Three key genes and 3-immune-cell signature were potential biomarkers for the prognosis of OSCC, and they may serve as potential targets for the treatment of OSCC patients.

Circ_0005320 promotes oral squamous cell carcinoma tumorigenesis by sponging microRNA-486-3p and microRNA-637

ABSTRACT Circ_0005320 was found to be elevated in oral squamous cell carcinoma (OSCC) and accelerated OSCC progression. Here, the potential mechanism of circ_0005320 in OSCC tumorigenesis was explored. The quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect the expression of circ_0005320, miR-486-3p, and miR-637. In vitro assays were conducted using cell counting kit-8, colony formation, transwell, angiogenesis, and flow cytometry assays. The targeting relationship between microRNA (miR)-486-3p and miR-637 or circ_0005320 was confirmed using the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway-related proteins were analyzed using Western blot. The murine xenograft model was established to perform in vivo assay. Circ_0005320 expression was higher in OSCC tissues and cells. Knockdown of circ_0005320 suppressed OSCC cell growth, migration, invasion, and induced cell apoptosis in vitro, as well as impeded tumor growth in vivo. Mechanistically, miR-486-3p or miR-637 were confirmed to be a target of circ_0005320. Moreover, the inhibitory effects of circ_0005320 silencing on OSCC growth were reversed by the inhibition of miR-486-3p or miR-637. We also found that circ_0005320-miR-486-3p/miR-637 axis mediated the activation of JAK2/STAT3 pathway. This study revealed a novel regulatory network of circ_0005320-miR-486-3p/miR-637 axis in OSCC progression, suggesting that circ_0005320 might be a potential biomarker and therapeutic target for OSCC.

Hepatocyte Growth Factor Overexpression Slows the Progression of 4NQO-Induced Oral Tumorigenesis.

ObjectivesTo investigate the role of hepatocyte growth factor (HGF)/c-Met signaling in oral malignant transformation.MethodsWe used immunohistochemistry to investigate HGF and c-Met expression in 53 oral squamous cell carcinoma (OSCC) specimens and 21 adjacent nontumor specimens and evaluated the associations between HGF and c-Met expression and clinicopathological parameters. Additionally, HGF-overexpression transgenic (HGF-Tg) and wild-type (Wt) mice were treated with 4-nitroquinoline-1-oxide (4NQO) to induce oral carcinogenesis for 16 weeks. At 16, 20, and 24 weeks, tongue lesions were collected for clinical observation; estimation of HGF, c-Met, and PCNA expression; apoptosis (TUNEL) assays; and RNA sequencing (RNA-seq).ResultsHGF and c-Met were positively expressed in 92.5% and 64% of OSCC samples, respectively. High HGF expression was significantly associated with smaller tumor size (p = 0.006) and inferior TNM stage (p = 0.032). No correlation between HGF and c-Met levels and other clinical parameters or prognosis was noted. In addition, HGF and c-Met expression was elevated in 4NQO-induced lesions of Wt mice. Compared with Wt mice, HGF-Tg mice have lower tumor incidence, number, volume, and lesion grade. In addition, the percentage of PCNA-positive cells in Wt mice was significantly higher than that in HGF-Tg mice at different time points. At 16 weeks, HGF-Tg mice exhibited less apoptotic cells compared with Wt mice (p < 0.000), and these levels gradually increased until the levels were greater than that of Wt mice at 24 weeks (p < 0.000). RNA-seq data revealed that 140 genes were upregulated and 137 genes were downregulated in HGF-Tg mice. KEGG enrichment analysis showed that upregulated differentially expressed genes (DEGs) are highly correlated with oxidative and metabolic signaling and that downregulated DEGs are related to MAPK and PI3K-AKT signaling.ConclusionsHGF and c-Met expression is upregulated in OSCC tissues and is associated with the occurrence and development of OSCC. HGF overexpression in normal oral epithelial tissue can inhibit 4NQO-induced tumorigenesis potentially through inhibiting proliferation and accelerating apoptosis via MAPK and PI3K-AKT signaling.

FTO demethylates YAP mRNA promoting oral squamous cell carcinoma tumorigenesis.

N6-methyladenosine (m6A) is the most common internal reversible modification of mRNA, which occurs on the N6 nitrogen of adenosine. Fat mass and obesity-associated (FTO) is a demethylase that erases m6A modification and has recently been linked to cancer. Herein, we explored the role of FTO in oral squamous cell carcinoma (OSCC). High FTO mRNA and protein levels were observed in OSCC cell lines and tissues as compared to normal controls. OSCC patients with high FTO displayed larger tumor size, higher TNM stage, poorer differentiation, and shorter survival time than those with low FTO. Stable knockdown of FTO inhibited OSCC cell viability, colony formation, and tumor growth. Further, FTO depletion increased YAP1 m6A modification at mRNA 3'-untranslated region, accelerating the degradation of YAP1 mRNA, a well-documented oncogene promoting OSCC progression. Importantly, nucleocytoplasmic shuttling of FTO is critical for YAP1 mRNA demethylation and decay following YTHDF2 reading and recognition. Our results highlight the role of FTO in regulating YAP1 mRNA stability, and targeting of FTO/YAP1 axis may be a promising intervention for OSCC patients.

EZH2 knockout in oral cavity basal epithelia causes more invasive squamous cell carcinomas.

Oral squamous cell carcinoma (oral SCC) is an aggressive disease and despite intensive treatments, 5-year survival rates for patients have remained low in the last 20 years. Enhancer of zeste homolog 2 (EZH2), part of polycomb repressive complex 2 (PRC2), is highly expressed in human oral SCC samples and cell lines and has been associated with greater epithelia-to-mesenchymal transition (EMT), invasion and metastasis. Here, we developed a tamoxifen-regulated, transgenic mouse line (KcEZH2) in which EZH2 is selectively knocked out (KO) in some tongue epithelial basal stem cells (SCs) in adult mice. EZH2 KO SCs do not show the H3K27me3 mark, as assessed by double-label immunofluorescence. We used this mouse line to assess EZH2 actions during oral tumorigenesis with our immunocompetent 4-nitroquinoline 1-oxide model of oral SCC. We report that higher percentages of mice with invasive SCCs and high-grade neoplastic lesions are observed in mice containing EZH2 KO SCs (KcEZH2-2TΔ and KcEZH2-5TΔ mice). Moreover, EZH2 expression does not correlate with the expression of markers of invasive SCCs. Finally, EZH2 KO cells that are E-cadherin+ are present at invasion fronts infiltrating underlying muscle tissue. Our findings indicate that the knockout of EZH2 in basal SCs of tongue epithelia results in more aggressive carcinomas, and this should be considered when targeting EZH2 as a therapeutic strategy.

Cigarette Smoke Containing Acrolein Upregulates EGFR Signaling Contributing to Oral Tumorigenesis In Vitro and In Vivo.

Simple SummaryOral squamous cell carcinoma (OSCC) is one of the most common smoking-related cancer types in the world. Better understanding of the pathophysiology of OSCC would lead to the development of novel therapeutic options. The epidermal growth factor receptor (EGFR) pathway plays a crucial role in the development of OSCC, and aberrant EGFR expression levels have been associated with smoking. Cigarette smoke contains large amounts of aldehydes such as acrolein, which is a highly reactive environmental toxin. In this study, our results present that acrolein is important in oncogenic transformation through activating the EGFR signaling pathway, contributing to oral carcinogenesis. To the best of our knowledge, this is the first study to provide molecular evidence, showing that cigarette smoke containing acrolein contributes to EGFR amplification and activation of downstream signaling in OSCC. Thus, acrolein might be a novel target for early detection and prevention of oral cancer in the future.Oral squamous cell carcinoma (OSCC) accounts for 80–90% of all intraoral malignant neoplasms. The single greatest risk factor for oral cancer is tobacco use, including cigarettes, cigars, chewing tobacco, and snuff. Aberrations of the epidermal growth factor receptor (EGFR) pathway features prominently in oral tumorigenesis and progression. It was shown that cigarette smoking (CS) is associated with worse prognosis in OSCC patients and overexpression of EGFR in tumor tissue. However, the mechanism by which cigarette smoking induced EGFR pathway activation remains to be fully elucidated. Acrolein, an IARC group 2A carcinogen, is a highly reactive aldehyde found in CS. Here we report that acrolein is capable of inducing tumorigenic transformation in normal human oral keratinocytes (NOK). The acrolein-transformed NOK cells showed EGFR copy number amplification, increased EGFR expression, and activation of downstream ERK and AKT signaling pathway. No p53 mutations were observed in acrolein-transformed NOK cells. Inhibiting EGFR pathway using an anti-EGFR antibody, cetuximab, inhibits tumor growth. Furthermore, by examining tissue sample from patients, we found an increased EGFR copy number was positively associated with acrolein-induced DNA damages in OSCC patients. Taken together, our results indicate that acrolein is important in tumorigenic transformation through amplification of EGFR and activating the downstream signaling pathway, contributing to oral carcinogenesis. This is the first study to provide molecular evidence showing that CS containing acrolein contributes to EGFR amplification in OSCC.

Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers.

Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancercell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.

Immune landscape and subtypes in primary resectable oral squamous cell carcinoma: prognostic significance and predictive of therapeutic response

BackgroundImmune landscape of cancer has been increasingly recognized as a key feature affecting disease progression, prognosis and therapeutic response. Here, we sought to comprehensively characterize the patterns of tumor-infiltrating immune...

Macrophage-Derived Exosomal miR-31-5p Promotes Oral Squamous Cell Carcinoma Tumourigenesis Through the Large Tumor Suppressor 2-Mediated Hippo Signalling Pathway.

Tumour-associated macrophages (TAMs) are thought to contribute to oral squamous cell carcinoma (OSCC) initiation and progression. However, the underlying mechanism through which TAMs foster OSCC progression is still unclear. This study intended to determine whether there are exclusively exosomal miRNAs-derived macrophages that are functionally necessary for OSCC progression. The phenotype of TAM recruitment in OSCC tissue samples was assessed, subsequently identifying the influence of M2 macrophages and exosomes derived from M2 macrophages on OSCC proliferation and tumorigenesis in vitro and in vivo. CD68 and CD163, the specific markers of M2 type macrophages, were upregulated in TAMs presented in intra-cancer tissues. M2 macrophages and M2 macrophage-derived exosomes (M2 exos) both can promote OSCC growth and tumorigenicity. An exosomal RNA-seq analysis was conducted to predict regulatory exosomal miRNAs related to OSCC growth, which determined miR-31-5p and LATS2 for subsequent experiments. Mechanistically, miR-31-5p was delivered to recipient OSCC cells through M2 exos and complementary pairing with the large tumor suppressor 2 (LATS2) coding sequence, thus suppressing the expression of LATS2 and inactivation the Hippo signaling pathway to support OSCC growth. Collectively, our findings demonstrate that M2 macrophage-derived exosomal miR- 31-5p can make tumor suppressor LATS2 gene inhibited and facilitate the progression of OSCC via inhibiting the Hippo signaling pathway, which possibly provides new targets for the molecular therapy of OSCC.

Differential Expression of Potential Biomarkers of Oral Squamous Cell Carcinoma Development.

To evaluate molecular epithelial changes, we investigated whether a profile of survivin, cyclin dependent kinase inhibitor 2A (CDKN2A), epidermal growth factor receptor (EGFR), polo like kinase 1 (PLK1), p63, p40 (Δnp63 isoform), cyclin D1 (CCND1) and BCL2 apoptosis regulator (BCL2) proteins could predict malignant transformation. Different tissue segments (tumor adjacent epithelium; dysplasia and tumor) from a total of 109 patients were analyzed by immunohistochemistry. An increased expression of survivin (p < 0.001), PLK1 (p = 0.001), and p63 (p < 0.001) in parallel to reduced immunostaining of p40 (p < 0.001) and BCL2 (p = 0.029) was observed among the tissue segments analyzed. Our study revealed that survivin, PLK1, p63, p40 and BCL2 play a role in oral tumorigenesis and represent promising biomarkers able to recognize mesenchymal phenotype induction in the transition from nonmalignant cells to tumor cells. These results reveals critical interaction between survivin, PLK1, p63, p40 promising proteins during invasive carcinoma development.

MicroRNAs as Modulators of Oral Tumorigenesis-A Focused Review.

Oral cancers constitute the majority of head and neck tumors, with a relatively high incidence and poor survival rate in developing countries. While the five-year survival rates of the oral cancer patients have increased to 65%, the overall survival for advanced stages has been at 27% for the past ten years, emphasizing the necessity for further understanding the etiology of the disease, diagnosis, and formulating possible novel treatment regimens. MicroRNAs (miRNAs), a family of small non-coding RNA, have emerged as master modulators of gene expression in various cellular and biological process. Aberrant expression of these dynamic molecules has been associated with many human diseases, including oral cancers. The deregulated miRNAs have been shown to control various oncogenic processes, including sustaining proliferative signaling, evading growth suppressors, resisting cell death activating invasion and metastasis, and inducing angiogenesis. Hence, the aberrant expression of miRNAs associated with oral cancers, makes them potential candidates for the investigation of functional markers, which will aid in the differential diagnosis, prognosis, and development of novel therapeutic regimens. This review presents a holistic insight into our understanding of the role of miRNAs in regulating various hallmarks of oral tumorigenesis.

A variant of H19 transcript regulates EMT and oral cancer progression.

Oral cancer is one of the most common malignant tumors of the head and neck, and it continues to represent a serious public health problem. Recent reports show the involvement of H19 long noncoding RNA (LncRNA) in oncogenesis but its mechanism associated with oral cancer remains unclear. Here, we identify an H19 transcript variant that lacks exon 4 in oral cancer specimens and carcinoma-derived cells. Depletion of H19 by short hairpin RNAs (shRNAs) targeting exon 1 but not exon 4 significantly inhibited oral cancer iCell-h120 cells growth and invasion in vitro and tumorigenesis of these cells in vivo. Through binding the ZEB1 mRNA, the variant H19 transcript without exon 4 promotes the expression of ZEB1 protein during epithelial-mesenchymal transition (EMT). Thus, these data reveal the role of a splicing events of H19LncRNA in oral tumorigenesis, and indicate that the splicing event of H19 can be served as potential therapeutic targets for oral cancer.

Correction to: Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis.

Unfortunately the book was published without correcting a typo in the author name in chapter 8. The author name has been corrected now to read as follows.