Fibronectin Type III Domain Containing 5 Contributes to Nab-paclitaxel Chemoresistance by Promoting Autophagy via the AMPK/mTOR Signaling Pathway in Hepatocellular Carcinoma Cells

Abstract Chemotherapy resistance is a huge challenge in the treatment of hepatocellular carcinoma because resistance to nab-paclitaxel largely affects the efficacy of chemotherapy. An increased expression of fibronectin type III domain containing 5 (FNDC5) in hepatocellular carcinoma cells can predict post-hepatectomy complications in patients with hepatocellular carcinoma and also stimulate proliferation and invasion of hepatocellular carcinoma cells; however, its role in the chemotherapy of hepatocellular carcinoma cells has never been evaluated. Thus, this study aimed to explore whether FNDC5 regulates chemoresistance in hepatocellular carcinoma. We identified by immunohistochemistry that hepatocellular carcinoma tissues had a higher FNDC5 expression than normal tissues adjacent to the cancer cells. Subsequently, knockdown of FNDC5 in hepatocellular carcinoma cells resulted in their diminished resistance to cell death after chemotherapy with nab-paclitaxel. By contrast, overexpression of FNDC5 in hepatocellular carcinoma cells increased the resistance of hepatocellular carcinoma cells to treatment. Moreover, FNDC5 mechanistically promoted autophagy via the AMPK/mTOR signaling pathway, thereby reducing cell death induced by nab-paclitaxel. Finally, we tested our hypothesis by conducting animal experiments. In conclusion, FNDC5 could be used as a biomarker for predicting chemotherapeutic efficacy in hepatocellular carcinoma treated with nab-paclitaxel chemotherapy, and as a therapeutic target to overcome resistance to nab-paclitaxel in hepatocellular carcinoma chemotherapy.