Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer.
Dharavath B, Butle A, Pal A, Desai S, Upadhyay P, Rane A, Khandelwal R, Manavalan S, Thorat R, Sonawane K, Vaish R, Gera P, Bal M, D'Cruz AK, Nair S, Dutt A.
Tongue cancer is a relatively common malignancy associated with severe disease and treatment-related morbidity. The presence of regional occult lymph node metastasis is one of the important factors for poor clinical outcomes. Lymph node metastasis is observed in 27-40% of early-stage tongue cancer patients. Presence of even a single cancer-positive lymph node leads to a poor 5-year survival of below 50%. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis. We previously reported over-expression of MMP10 (Oral Oncology 2017) in tongue tumors to be associated with nodal metastases in early-stage tongue cancer patients.
Here, we analyzed 219 early-stage tongue cancer resected specimens for MMP10 expression obtained from patients before surgery, including phase 3 trial N-zero clinical trial samples. We find upregulation of MMP10 in 86% of primary tongue tumors with lymph node metastases (p<0.0001). We show miR-944 negatively regulates MMP10 by targeting its 3'-UTR and overexpression of miR-944 or loss of MMP10 suppresses proliferation, migration and invasion of tongue cancer cells in vitro and impedes nodal metastasis in orthotopic tongue cancer mouse model. Importantly, overexpression of MMP10 induces tumor growth and nodal metastasis mediated through the AXL signaling pathway inducing epithelial mesenchymal transition (EMT) phenotype. Knockdown of AXL suppresses MMP10-mediated proliferation, migration and invasion of tongue cancer cells, indicating AXL to be a candidate therapeutic target in tongue cancer. To summarize, our study establish miR-944/MMP10/AXL- axis underlie lymph node metastases among early-stage tongue cancer patients. Additionally, low expression of miR-944 or overexpression of MMP10 as a prognostic biomarker could also help predict nodal metastasis in tongue cancer, an assessment that awaits designing a larger prospective randomized clinical trial.