Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth leading malignancy worldwide. OSCC is an aggressive tumor and its prognosis has exhibited little improvement in the last three decades. Comprehensive elucidation of OSCC’s molecular mechanism is imperative for early detection and treatment, improving patient survival. Based on broadly accepted notions, OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens. In 2011, research revealed 10 key alterations fundamental to cancer cell development: sustaining proliferative signaling, evading growth suppressors, avoiding immune destruction, activating invasion and metastasis, tumor-promoting inflammation, enabling replicative immortality, inducing angiogenesis, genome instability and mutation, resisting cell death, and deregulating energetics. This review describes molecular pathological findings on conventional and novel hallmarks of OSCC prognostic factors. In addition, the review summarizes the functions and roles of several molecules as novel OSCC prognosticators.

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Background:MicroRNA (miRNA)-126 (miR-126) is an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7). However, the role of miR-126 in cancer is controversial.Methods:We examined the function of miR-126 in oral squamous cell carcinoma (OSCC) cells. Furthermore, a series of 118 cases with OSCC were evaluated for the expression levels of miR-126.Results:MicroRNA-126 (miR-126) was associated with cell growth and regulation of vascular endothelial growth factor-A activity, and demethylation treatment increased expression levels of miR-126 and EGFL7 in OSCC cells. A significant association was found between miR-126 expression and tumour progression, nodal metastasis, vessel density, or poor prognosis in OSCC cases. In the multivariate analysis, decreased miR-126 expression was strongly correlated with disease-free survival.Conclusion:The present results suggest that miR-126 might be a useful diagnostic and therapeutic target in OSCC.

Melanoma inhibitory activity (MIA) is an 11-kDa secretory protein isolated from malignant melanoma cells that is correlated with invasion and metastasis in various human malignancies. We examined MIA expression in 62 oral squamous cell carcinomas (OSCC) by immunohistochemistry. MIA expression was significantly associated with nodal metastasis (P = 0.00018). MIA expression was also associated with expression of high mobility group box-1 (HMGB1) (P < 0.0001) and lymph vessel density (P < 0.0001). Expression levels of MIA, HMGB1, nuclear factor kB (NFkB) p65 and HMGB1-NFkB p65 binding were significantly higher in a metastatic human OSCC cell line (HSC3) than those in a non-metastatic OSCC cell line (HSC4). H ead and neck cancer is the sixth most common malignancy worldwide and the first leading cause of cancer death in South Asia.(1) About 300 000 patients develop OSCC every year in the world.(2,3) OSCC has a high potential for nodal metastasis and locoregional invasion, (4) from which over 50% of patients die.(5,6) To control lymph-node metastasis of OSCC, we need to study the molecular aspects of the mechanism of metastasis.MIA is an 11-kDa secretory protein isolated from supernatants of HTZ-19 malignant melanoma cells, (7,8) the gene locus of which is mapped to chromosome 19q13.32-13.33.(9) Although previous reports indicated that MIA is correlated with invasion and metastasis in malignant melanoma, (10)(11)(12) breast cancer,chondrosarcoma, (13) glioma, (14) and pancreatic cancer,the definite functions of MIA for cancer cells are still unclear.HMGB1 has a dual role as an extracellular secretory protein and a chromosomal structural protein.(16) HMGB1 works as a cytokine or a growth factor in neural ontogenesis, septic inflammation and neoplasm. HMGB1 is also considered an amphoterin, which is isolated as a motility factor in neurite outgrowth.(17) We previously reported coexpression of HMGB1 and receptor for advanced glycation end products (RAGE), which is a major membrane receptor for HMGB1 and is significantly associated with tumor progression and metastasis (18)(19)(20)(21)(22)(23)(24) and suppression of tumor-associated macrophages. (25,26) As a chromatin structural protein, HMGB1 participates in gene expression, DNA repair and functions of the p53 family.(27) Recently, HMGB1 was revealed to interact with NFkB p65 to accelerate MIA expression. (28,29) HMGB1 and NFkB p65 concurrently bind to a 30-bp region in the promoter region of the MIA gene designated as the highly conserved region (HCR).MIA is suspected to play an important role as a pro-metastatic factor in HMGB1-overexpressing cancers. In the present study, we analyzed the relationship between MIA expression and nodal metastasis and HMGB1 expression in human OSCC. Materials and MethodsTumor specimens. Sixty-two formalin-fixed, paraffin-embedded specimens of primary OSCC were randomly selected at Nara Medical University Hospital, Kashihara, Japan. None of the samples was treated using neo-adjuvant therapy. Medical records and prognostic follow-up data w...