Human papillomavirus 16 (HPV-16) is an important risk factor in head and neck cancer (HNC). Studies suggest that miRNAs play an important role in cancer; however, their role in HPV-mediated oncogenesis remains largely unknown. We investigated the role of miRNAs with HPV-16 as putative target in HPV-16-mediated cancers. Using tools, we identified miRNAs with putative binding sequences on HPV-16 miRNAs. Hsa-miR-139-3p was identified as best candidate miRNA by luciferase reporter assay and was found to be significantly downregulated in HPV-16-positive tissues and cell lines. Overexpression/inhibition studies were performed to determine the role of miRNA in regulating oncogenic pathways. Hsa-miR-139-3p was found to target high-risk HPV-16 oncogenic proteins and revive major tumor suppressor proteins (p53, p21, and p16). This resulted in inhibition of cell proliferation and cell migration, cell-cycle arrest at G-M phase and increased cell death of HPV-16-positive cells. Analysis of The Cancer Genome Atlas (TCGA) data showed decreased expression of Hsa-miR-139-3p in HPV-16-positive HNC and cervical cancer cases, and its higher expression correlated with better survival outcome in both cases. Increased DNA methylation of Hsa-miR-139-3p harboring gene PDE2A at its promoter/CpG islands was observed in HPV-16-positive tissues and cell lines, which further correlated with Hsa-miR-139-3p expression, suggesting its role in regulating Hsa-miR-139-3p expression. Furthermore, we observed an increased sensitization of Hsa-miR-139-3p overexpressed HPV-16-positive cells to chemotherapeutic drugs (cisplatin and 5-fluorouracil). HPV-16-mediated downregulation of Hsa-miR-139-3p may promote oncogenesis in HNC and cervical cancer. .

Head and neck squamous cell carcinomas (HNSCC) are one of the most common cancers worldwide, accounting for almost 50% of all malignancies in developing nations. Autophagy is a catabolic process involving turnover of long-lived proteins and organelles and is an important mechanism for cell survival under stress conditions. Autophagy has been shown to play a pivotal role in etio-pathogenesis of several cancers. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis, or defective apoptosis rendering immortalized epithelial cells highly tumorigenic. Autophagy has been found to buffer metabolic stress and may help in cell survival; however, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors. Therefore, autophagy acts as a double-edged sword in cancer therapeutics. Role of autophagy in pathophysiology and as a potential cancer therapeutics is a subject of intensive research. This review will focus on the role of autophagy and how it contributes to the pathogenesis and overcoming therapeutic resistance in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high recurrence, metastasis, and poor treatment outcome. Recent studies have reported that non-coding RNA (ncRNA) might play critical role in regulating different types of cancer. MicroRNAs (miRs) are short ncRNAs (20-25 nucleotides) responsible for post-transcriptional regulation of gene expression and may have a role in oncogenesis by acting as oncomiRs or tumor suppressor miRs. Long non-coding RNAs (lncRNAs) are heterogenous group of ncRNAs more than 200 nucleotides long, can act in cis and/or in trans, and have been also implicated in carcinogenesis. These molecules have been suggested to be promising candidates as diagnostic and prognostic biomarkers and for development of novel therapeutic approaches. In this review, we have summarized recent findings on role of these ncRNAs in HPV-negative (HPV-ve) and HPV-positive (HPV+ve) HNSCC. The available literature supports differential expression of both microRNAs and long non-coding RNAs, which include oncogenic ncRNAs (miR-21, miR-31, miR-155, miR-211, HOTAIR, and MALAT1) and tumor suppressor ncRNAs (let7d, miR-17, miR-375, miR-139, and MEG3) in HPV+ve HNSCC tumors as compared to HPV-ve tumors and they have distinct role in the pathophysiology of these two types of HNSCCs.

Cadherin‐23 (Cdh23), a long‐chain non‐classical cadherin, exhibits strong homophilic and heterophilic binding. The physiological relevance of strong heterophilic binding with protocadherin‐15 at neuroepithelial tip links is well‐studied. However, the role of Cdh23 homodimers in physiology is less understood, despite its widespread expression at the cell boundaries of various human and mouse tissues, including kidney, muscle, testes, and heart. Here, we performed immunofluorescence studies that revealed that Cdh23 is present as distinct puncta at the cell–cell boundaries of cancer cells. Analysis of patient data and quantitative estimation of Cdh23 in human tissues (normal and tumor) also indicated that Cdh23 is down‐regulated via promoter methylation in lung adenocarcinoma (AD) and esophageal squamous cell carcinoma (SCC) cells; we also observed a clear inverse correlation between Cdh23 expression and cancer metastasis. Using HEK 293T cells and four types of cancer cells differentially expressing Cdh23, we observed that cell migration was faster in cells with reduced levels of Cdh23 expression. The cell migration rate in cancer cells is further accelerated by the presence of excretory isoforms of Cdh23, which loosen its cell‐adhesion ability by competitive binding. Overall, our data indicate the role of Cdh23 as a suppressor of cell migration.

Cadherin-23, a giant atypical cadherin, form homophilic interactions at the cell-cell junction of epithelial cells and heterophilic interactions with protocadherin-15 at the tip links of neuroepithelial cells. While the molecular structure of the heterodimer is solved, the homodimer structure is yet to be resolved. The homodimers play an essential role in cell-cell adhesion as the downregulation of cadherin-23 in cancers loosen the intercellular junction resulting in faster migration of cancer cells and a significant drop in patient survival. In vitro studies have measured a stronger aggregation propensity of cadherin-23 compared to typical E-cadherin. Here, we deciphered the unique trans-homodimer structure of cadherin-23 in solution and show that it consists of two electrostatic-based interfaces extended up to two terminal domains. The interface is robust, with a low off-rate of~8 9 10 À4 s À1 that supports its strong aggregation propensity. We identified a point mutation, E78K, that disrupts this binding. Interestingly, a mutation at the interface was reported in skin cancer. Overall, the structural basis of the strong cadherin-23 adhesion may have far-reaching applications in the fields of mechanobiology and cancer.