Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGFß/Smad2-induced epithelial-mesenchymal transition in gastric cancer.

ABSTRACT

Chemotherapy is one of the vital treatments for gastric cancer (GC) patients, especially those suffering advanced stages. Chemoresistance results in tumor relapse, leading to poor prognosis in GC patients; thus, identifying key regulators in this process might provide novel clues for GC therapy. Herein, we identify hyaluronan-mediated motility receptor (HMMR) as a key regulator of chemoresistance in GC. HMMR was found to be substantially up-regulated in 5-fluorouracil (5-Fu)-resistant GC biopsies and cell lines. High expression of HMMR significantly correlates with tumor relapse and predicts poorer prognosis in GC patients. Moreover, we observed that HMMR induced epithelial-mesenchymal transition and increased the cancer stem cell properties of GC, thus rendering resistance to chemotherapy. Importantly, silencing of HMMR effectively increased the susceptibility to 5-Fu therapy both in vitro and in vivo. Furthermore, we demonstrated that HMMR activates the TGF-ß/Smad2 signaling pathway, which was required for the HMMR-mediated oncogenic effects and exhibited significant clinical relevance with HMMR expression. These findings reveal a critical role for HMMR in the chemoresistance of GC and suggest that HMMR might be a potential prognostic marker or therapeutic target against the disease.-Zhang, H., Ren, L., Ding, Y., Li, F., Chen, X., Ouyang, Y., Zhang, Y., Zhang, D. Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGFß/Smad2-induced epithelial-mesenchymal transition in gastric cancer.