CXCL11 promotes self-renewal and tumorigenicity of α2δ1+ liver tumor-initiating cells through CXCR3/ERK1/2 signaling

Tumor-initiating cells (TICs), which are responsible for sustaining tumor growth and recurrence, rely on several regulatory factors. However, the mechanism of inflammation-related molecules in the acquisition and maintenance of TIC properties in hepatocellular carcinoma (HCC) remains elusive. We previously demonstrated that the voltage-gated calcium channel alpha 2 delta 1 subunit is a functional surface marker of HCC TICs. Here, we found that the expression of an inflammation-related molecule C-X-C motif chemokine 11 (CXCL11) was significantly upregulated in alpha 2 delta 1 HCC TICs and that CXCL11 induced the expression of stem cell-related genes, such as BMI1, NANOG, MDR1, ABCG2, and CACNA2D1. Furthermore, CXCL11 could promote the acquisition and maintenance of self-renewal, tumorigenic, and chemoresistance properties of alpha 2 delta 1(+) HCC TICs by activating the extracellular signal-regulated kinase (ERK1/2) through its affinity receptor CXCR3. Collectively, our results suggest that CXCL11 may positively regulate the stemness of alpha 2 delta 1(+) HCC TICs via ERK1/2 activation through an autocrine signaling pathway.