XBP1‐elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR‐22/lncRNA/KAT6B‐dependent NF‐κB signalling

Abstract

Background: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour-promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells.Methods: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. Results: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)-and basic fibroblast growth factor (bFGF)-based extracellular environments via cytotoxic treatment-induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)-dependent nuclear factor-kappa B (NF-κB) signalling in living tumour cells. As direct targets of NF-κB, miR-22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) Xiaoting Jia, Ge Wang and Lihong Wu contributed equally to the work.