Recent studies showed that lncRNA CASC9 was upregulated and acted as an oncogene in a variety of tumors. However, the expression and biological functions of CASC9 in oral squamous cell carcinoma (OSCC) remain unknown. In this study, we found for the first time that CASC9 was remarkably upregulated in OSCC tissues and cell lines compared with paired noncancerous tissues and normal oral epithelial cells. Highly expressed CASC9 is strongly associated with tumor size, clinical stage, regional lymph node metastasis and overall survival time in OSCC patients. In vitro, CASC9 knockdown in OSCC cells SCC15 and CAL27 significantly promotes autophagy and apoptosis, while inhibiting proliferation. Moreover, the expression levels of p-AKT, p-mTOR, P62 and BCL-2 were significantly decreased, while the expression levels of BAX and the LC3BII/LC3BI ratio were increased in CASC9-knockdown SCC15 and CAL27 cells. After the addition of the AKT activator SC79 in CASC9-knockdown SCC15 and CAL27 cells, we found that the increased autophagy and apoptosis were remarkably rescued. Furthermore, the increased apoptosis was remarkably rescued in CASC9-knockdown OSCC cells treated with the autophagy inhibitor Autophinib. In addition, CASC9 depletion suppressed tumor growth in vivo. In conclusion, our findings demonstrate that lncRNA CASC9 promotes OSCC progression through enhancing cell proliferation and suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway. CASC9 could potentially be used as a valuable biomarker for OSCC diagnosis and prognosis.

Integrin-linked kinase (ILK), an intracellular protein with serine/threonine protein kinase activities, plays a key role in integrin mediated cell-excellular matrix interactions, regulating cell proliferation, apoptosis, differentiation, and migration. ILK has been implicated in the development and progression in several malignancies. However, the role of ILK and ILK-mediated epithelial-mensenchymal transition (EMT) in the progression of oral squamous cell carcinoma (OSCC) has not been well understood. Here, by immunohistochemistry, we studied the expression of ILK, Snail, E-cadherin and N-cadherin in 98 primary OSCC specimens and analyzed their correlations with clinicopathologic profiles and clinical outcome. We also investigated the expression of ILK in 42 corresponding lymph node metastases. Positive expression of ILK protein was detected in 87.8 % of the primary tumors and 100 % of metastatic lesions. Increased ILK expression was correlated strongly with enhanced tumor invasion, higher tumor grade, advanced clinical stage, positive lymph node status and increased risk of recurrence. Higher ILK expression was also observed in lymph node metastases in comparison with the corresponding primary tumor. Moreover, up-regulation of Snail and N-cadherin and down-regulation of E-cadherin correlated significantly with both ILK over-expression and tumor invasion. Patients with higher ILK expression exhibited shorter disease-free survival while those with absent E-cadherin expression exhibited shorter overall and disease-free survival. Taken together, our results suggest that ILK may have an important role in progression and metastasis of OSCC, possibly through EMT involving up-regulation of Snail and consequent aberrant expression of E-cadherin and N-cadherin. ILK should be considered as a critical prognostic indicator for patients with OSCC.

Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase‑8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was significantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2‑negative expression had a significantly shorter survival time than those with PER2‑positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase‑8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase‑8 pathways.

Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P<0.05). PER1 expression was significantly down-regulated in patients of T3∼T4 staging and those with lymph node metastasis compared to that of T1∼T2 staging and those without lymph node metastasis (P<0.05), respectively. PER1 mRNA expression, MI and tumor weight had significant differences among the 4 time groups, which PI all confirmed to circadian rhythms. MI, PI, MMP-2 mRNA and tumor weight had negative correlation with PER1 mRNA expression. Peak value of PER1 mRNA expression and trough values of MI, PI and tumor weight all appeared in middle activity phase, whereas trough value of PER1 mRNA expression and peak values of MI, PI and tumor weight all occurred in middle rest phase. Our study suggested that aberrant expression of PER1 had significant correlation with the growth, proliferation and metastasis of BSCC and it might act as an anti-oncogene.

CAFs may play critical roles in OSCC progression as an inducer of tumor invasion, angiogenesis, and lymphangiogenesis. Therapeutic strategies targeting CAFs against OSCC is promising and need further exploration.

Head and neck cancer (HNC) is a common malignant tumor, but traditional therapeutic methods have unsatisfactory curative effects and many complications occur. Hence, there is an urgent need to develop therapeutic methods that can elicit curative effects as well as low toxic and few side effects. With the development of cancer molecular biology and immunology, targeted therapy for immune checkpoints of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown enormous development prospects for HNC treatment. Groundbreaking progress has been achieved in the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). This review describes current treatment by PD-1- and PD-L1-targeted drugs for HNC.

Previous studies have shown that the aberrant expression of period circadian clock 2 (Per2) is closely related to the occurrence and development of cancers, but the specific mechanism remains unclear. In the present study, we used shRNA to downregulate Per2 in oral squamous cell carcinoma (OSCC) Tca8113 cells, and then detected the alterations in cell cycle, cell proliferation and apoptosis by flow cytometric analysis and mRNA expression alterations in all the important genes in the cyclin/cyclin-dependent protein kinase (CDK)/cyclin-dependent kinase inhibitor (CKI) cell cycle network by RT-qPCR. We found that in the Tca8113 cells, after Per2 downregulation, the mRNA expression levels of cyclin A2, B1 and D1, CDK4, CDK6 and E2F1 were significantly increased (P<0.05), the mRNA expression levels of p53, p16 and p21 were significantly decreased (P<0.05), cell proliferation was significantly higher (P<0.05), apoptosis was significantly lower (P<0.05) and the number of cells in the G1/G0 phase was significantly decreased (P<0.05). The present study proves that in OSCC, clock gene Per2 plays an important role in cell cycle progression and the balance of cell proliferation and apoptosis by regulation of the cyclin/CDK/CKI cell cycle network. Further research on Per2 may provide a new effective molecular target for cancer treatments.

Abnormal expression of the clock gene PER1 is highly correlated with carcinogenesis and the development of malignant tumors. Here, we designed short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. shRNA-mediated PER1 knockdown promoted SCC15 cell growth, proliferation, apoptosis resistance, migration and invasion in vitro. PER1 knockdown also increased the cells' expression of KI-67, MDM2, BCL-2, MMP2 and MMP9 mRNA, and decreased expression of C-MYC, p53, BAX and TIMP-2. In BALB/c nu/nu nude mice subcutaneously injected with SCC15 cells, PER1 knockdown in the cells enhanced tumor development, leading to increased tumor weights and volumes. These results suggest that PER1 is an important tumor suppressor gene and may be a useful molecular target for the treatment of cancer.