Novel Biomarker for predicting the spread of Tongue cancer

Tongue cancer is a type of oral cancer that forms in the front two-thirds of the tongue. A high prevalence of tobacco and alcohol use, as well as a low accuracy in detecting its spread in the early stages are the factors that contribute to the high incidence of tongue cancer in India. About 30% of tongue cancer patients develop occult (hidden) metastases or a subclinical disease spread to surrounding lymph nodes. This reduces their chances of survival. The risk for nodal metastases is assessed by physical examination and by imaging tests like CT or MRI scans. However, these techniques in practice are unreliable and likely to miss the detection of occult lymph node metastases. Due to its inaccuracy in finding occult metastases, treatment options for tongue cancer patients include the surgical removal of lymph nodes together with the primary tongue tumour. However, surgical removal of lymph nodes is linked with severe morbidity and is unnecessary in about 70% of patients without nodal metastases. Hence, precise prognostic indicators to predict the possibility of metastases in these individuals is a huge unmet need.

In this study, we identified a predictive biomarker for the identification of tongue cancer patients with lymph node metastasis in the early stage of the disease. We found that a protein called Matrix metalloproteinase-10 (MMP10) is over-expressed in 86% of tongue cancer patients with lymph node metastases. This means that measuring MMP10 expression could be used to predict the likelihood of lymph node metastases in these patients, sparing 70 to 80% of patients from morbid neck dissection (surgical removal of lymph nodes). We also identified a microRNA, miR-944, that negatively affects the levels of MMP10 by directly binding to the regulatory region of the gene and interfering with its molecular processing. Using biochemical and cell-based experiments, we also showed that low levels of MMP10 protein or higher expression levels of miR-944 inhibit the proliferation, migration and dissemination of tongue cancer cells. We verified these findings by using a complex orthotopic tongue cancer mouse model. Through the study of mouse tongue cancers, it was possible to demonstrate that decrease of MMP10 in mouse tongue tumours prevented lymph nodes and distant metastases. We also found that MMP10 regulates metastasis of tongue cancer cells by upregulating genes essential for epithelial-mesenchymal transition, importantly, a tyrosine kinase gene, AXL, which mediates nodal and distant metastasis. Consistent with these findings, a study of oral cancer data from the Caucasian population reveals that overexpression of MMP10 or AXL correlates positively with poor survival in individuals with tongue cancer.

Overall, our findings demonstrate that the miR-944/MMP10/AXL– axis underpins lymph node metastases in tongue cancer. And screening for expression of miR-944 or MMP10 could serve as prognostic biomarkers for the prediction of nodal metastases in tongue cancer and aid in the elimination of misdiagnosis, sparing 70 to 80% of patients from morbid neck dissection. These findings may enhance the treatment and prognosis of patients with tongue cancer.