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Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation

Oncogene volume 37, pages 3514–3527 (2018)Cite this article

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Abstract

Recent studies indicated that insufficient radiofrequency ablation (RFA) could endow hepatocellular carcinoma (HCC) with higher aggressive potential. Stress-induced phosphoprotein 1 (STIP1), which was found highly expressed in HCC, is a chaperone molecule mediating cell homeostasis under thermal stress. We aimed to explore the role of STIP1 on the metastasis of residual HCC after RFA. Mice model with orthotopic HCC implants or caudal vein injection were employed to assess potential of lung metastasis and/or intrahepatic metastasis (IHM) of HCC cells. Cell culture model was used to determine cell invasion, mesenchymal marker genes expression, and underlying molecular mechanisms. Clinical specimens were collected to analyze the relationship between STIP1 and clinical outcome. We found that insufficient RFA elicited more IHM of HCCLM3 tumors, which could be reduced by silencing STIP1. Knockdown of STIP1 also significantly decreased lung metastatic potential of HCCLM3 cells. In vitro, HCCLM3 and HepG2 displayed a spindle-shaped morphology with upregulation of STIP1 and mesenchymal markers after sublethal heat exposure. Mechanistically, heat exposure induced the formation of STIP1-heat shock protein 90 (HSP90) complex, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription. Blocking the HSP90–STIP1 complex reduced the invasive potential of HCC cells after heat exposure. Using clinical specimen, we found that STIP1 was expressed significantly higher in metastatic tumor tissues and in sera from metastatic HCC patients (p < 0.05). The high expression of STIP1 was significantly linked to shorter recurrence-free survival (p < 0.05). To sum up, our study found that STIP1 is positively associated with the sublethal heat-induced cancer cell metastasis through mediating the mesenchymal gene transcription. Blocking STIP1 activity may suppress HCC cell metastatic potential after RFA.

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Acknowledgements

We wish to appreciate Dr. Bing Liao and Dr. Zhengkai Cao for reviewing our immunohistochemical staining data.

Author contributions

Conception and design: SP, MK. Development of methodology: SP, MK. Acquisition of data: SP, TS, JL, YW, ZD. Analysis and interpretation of data: SP, TS, JL, MK. Writing, review and/or revision of the manuscript: SP, QZ, MK. Administrative, technical, or material support: LX, SC, ZP. Study supervision: MK.

Funding

This work was supported by the National Natural Science Foundation of China (81470817, 81771958), the Guangdong Science and Technology Plan (2016A020215189, 2014A020212396), the National Natural Science Foundation of Guangdong (2015A030311039) and the Guangzhou Science and Technology Plan (201704020099).

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    Authors and Affiliations

    1. Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

      Tianhong Su, Junbin Liao, Zihao Dai, Yifei Wang & Ming Kuang

    2. Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

      Lixia Xu & Sui Peng

    3. Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

      Shuling Chen & Ming Kuang

    4. Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

      Zhenwei Peng & Sui Peng

    5. Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA

      Qiuyang Zhang

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    Correspondence to Sui Peng or Ming Kuang.

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    These authors contributed equally: Tianhong Su, Junbin Liao, Zihao Dai.

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    Su, T., Liao, J., Dai, Z. et al. Stress-induced phosphoprotein 1 mediates hepatocellular carcinoma metastasis after insufficient radiofrequency ablation. Oncogene 37, 3514–3527 (2018). https://doi.org/10.1038/s41388-018-0169-4

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