A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

doi:10.1158/0008-5472.CAN-20-3175

. 2021 Jun 1;81(11):3036-3050.

doi: 10.1158/0008-5472.CAN-20-3175. Epub 2021 Feb 22.

A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

Yan Meng^#^{1

2}, Qiudong Zhao^#¹, Liwei An^#³, Shi Jiao⁴, Rong Li¹, Yan Sang¹, Jianping Liao¹, Pingping Nie⁴, Fuping Wen⁴, Junyi Ju³, Zhaocai Zhou^{5

6}, Lixin Wei⁷

Affiliations

¹ Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
² School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
³ Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China.
⁴ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁵ Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China. weilixin_smmu@163.com zczhou@sibcb.ac.cn.
⁶ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁷ Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. weilixin_smmu@163.com zczhou@sibcb.ac.cn.

^# Contributed equally.

PMID: 33619115
DOI: 10.1158/0008-5472.CAN-20-3175

A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

Yan Meng et al. Cancer Res. 2021.

. 2021 Jun 1;81(11):3036-3050.

doi: 10.1158/0008-5472.CAN-20-3175. Epub 2021 Feb 22.

Authors

Yan Meng^#^{1

2}, Qiudong Zhao^#¹, Liwei An^#³, Shi Jiao⁴, Rong Li¹, Yan Sang¹, Jianping Liao¹, Pingping Nie⁴, Fuping Wen⁴, Junyi Ju³, Zhaocai Zhou^{5

6}, Lixin Wei⁷

Affiliations

¹ Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
² School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
³ Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China.
⁴ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁵ Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, Tongji University School of Medicine, Shanghai, China. weilixin_smmu@163.com zczhou@sibcb.ac.cn.
⁶ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
⁷ Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. weilixin_smmu@163.com zczhou@sibcb.ac.cn.

^# Contributed equally.

PMID: 33619115
DOI: 10.1158/0008-5472.CAN-20-3175

Abstract

Most primary liver cancer (PLC) cases progress mainly due to underlying chronic liver inflammation, yet the underlying mechanisms of inflammation-mediated PLC remain unclear. Here we uncover a TNF receptor II (TNFR2)-hnRNPK-YAP signaling axis in hepatic progenitor cells (HPC) essential for PLC development. TNFR2, but not TNF receptor I (TNFR1), was required for TNFα-induced activation of YAP during malignant transformation of HPCs and liver tumorigenesis. Mechanistically, heterogeneous nuclear ribonuclear protein K (hnRNPK) acted downstream of TNFα-TNFR2 signaling to directly interact with and stabilize YAP on target gene promoters genome-wide, therefore coregulating the expression of YAP target genes. Single-cell RNA sequencing confirmed the association of TNFR2-hnRNPK with YAP expression and the pathologic importance of HPC. Accordingly, expressions of TNFR2, hnRNPK, and YAP were all upregulated in PLC tissues and were strongly associated with poor prognosis of PLC including patient survival. Collectively, this study clarifies the differential roles of TNFRs in HPC-mediated tumorigenesis, uncovering a TNFR2-hnRNPK-centered mechanistic link between the TNFα-mediated inflammatory milieu and YAP activation in HPCs during PLC development. SIGNIFICANCE: This work defines how hnRNPK links TNFα signaling and Hippo pathway transcription coactivator YAP in hepatic progenitor cells during primary liver tumorigenesis.

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References

1. Lu J, Wang J, Ling D. Surface engineering of nanoparticles for targeted delivery to hepatocellular carcinoma. Small. 2018;14.
1. Li L, Wang H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016;379:191–7.
1. di Bello G, Vendemiale G, Bellanti F. Redox cell signaling and hepatic progenitor cells. Eur J Cell Biol. 2018;97:546–56.
1. Tummala KS, Brandt M, Teijeiro A, Grana O, Schwabe RF, Perna C, et al. Hepatocellular carcinomas originate predominantly from hepatocytes and benign lesions from hepatic progenitor cells. Cell Rep. 2017;19:584–600.
1. Hou XJ, Ye F, Li XY, Liu WT, Jing YY, Han ZP, et al. Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol. 2018;326:52–9.

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[1] Lu J, Wang J, Ling D. Surface engineering of nanoparticles for targeted delivery to hepatocellular carcinoma. Small. 2018;14.

[2] Lu J, Wang J, Ling D. Surface engineering of nanoparticles for targeted delivery to hepatocellular carcinoma. Small. 2018;14.

[3] Li L, Wang H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016;379:191–7.

[4] Li L, Wang H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016;379:191–7.

[5] di Bello G, Vendemiale G, Bellanti F. Redox cell signaling and hepatic progenitor cells. Eur J Cell Biol. 2018;97:546–56.

[6] di Bello G, Vendemiale G, Bellanti F. Redox cell signaling and hepatic progenitor cells. Eur J Cell Biol. 2018;97:546–56.

[7] Tummala KS, Brandt M, Teijeiro A, Grana O, Schwabe RF, Perna C, et al. Hepatocellular carcinomas originate predominantly from hepatocytes and benign lesions from hepatic progenitor cells. Cell Rep. 2017;19:584–600.

[8] Tummala KS, Brandt M, Teijeiro A, Grana O, Schwabe RF, Perna C, et al. Hepatocellular carcinomas originate predominantly from hepatocytes and benign lesions from hepatic progenitor cells. Cell Rep. 2017;19:584–600.

[9] Hou XJ, Ye F, Li XY, Liu WT, Jing YY, Han ZP, et al. Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol. 2018;326:52–9.

[10] Hou XJ, Ye F, Li XY, Liu WT, Jing YY, Han ZP, et al. Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol. 2018;326:52–9.

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A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

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A TNFR2-hnRNPK Axis Promotes Primary Liver Cancer Development via Activation of YAP Signaling in Hepatic Progenitor Cells

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