Crosstalk between heat shock factor 1 and signal transducer and activator of transcription 3 mediated by interleukin‐8 autocrine signaling maintains the cancer stem cell phenotype in liver cancer

• DOI: 10.1111/jgh.16040
• Publication Date: 2022-10-27T10:30:39Z
• Authors: Zhengyan Yang; Wenjuan Wan; Pai Zhang; Shuangfeng Wang; Zhi Zhao; Jingrui Xue; Mengzhuo Yao; Yiwei Zhao; Weifeng Zheng; Baohua Niu; Mingli Wang; Hui Li; Weikai Guo; Zhiguang Ren; Yanzhong Hu
• Keywords: STAT3 Transcription Factor; 0303 health sciences; Interleukin-8; Liver Neoplasms; 3. Good health; Autocrine Communication; 03 medical and health sciences; Heat Shock Transcription Factors; Cell Line, Tumor; Neoplastic Stem Cells; Humans; Neoplasm Recurrence, Local; Signal Transduction

AbstractBackground and AimLiver cancer stem cells (LCSCs) cause therapeutic refractoriness and relapse in hepatocellular carcinoma. Heat shock factor 1 (HSF1) plays versatile roles in multiple cancers. However, the role of HSF1 in LCSCs is not well understood. This study investigated the function and signal mechanisms of HSF1 in maintaining LCSC phenotypes.MethodsWe established two LCSC lines, HepG2‐R and HuH‐7‐R. Constitutive activation of HSF1 was observed in these LCSCs. Specific short hairpin RNAs (shRNAs) and chemical inhibitors were used to identify the relationship between HSF1 expression and LCSCs phenotypes.ResultsWe revealed a concomitant activation modality involving HSF1 and STAT3 in LCSCs and liver cancer tissues. We also found that liver cancer patients whose HSF1 and STAT3 mRNA expression levels were high presented with unfavorable clinicopathological characteristics. Moreover, the secretion of interleukin‐8 (IL‐8) was elevated in the LCSC medium and was directly regulated by HSF1 at the transcriptional level. In turn, IL‐8 activated HSF1 and STAT3 signaling, and a neutralizing IL‐8 antibody inhibited HSF1 and STAT3 activity, reduced cancer stem cell marker expression, and decreased LCSC microsphere formation. Simultaneous intervention with HSF1 and STAT3 led to synergistically suppressed stemness acquisition and growth suppression in the LCSCs in vivo and in vitro.ConclusionsOur study indicates that IL‐8 mediates the crosstalk between the HSF1 and Stat3 signaling pathways in LCSCs and that the combined targeting of HSF1 and STAT3 is a promising treatment strategy for patients with advanced liver cancer.