Skip to main content

Advertisement

Springer Nature Link
Log in

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

The treatment of hepatocellular carcinoma (HCC) has been dominated by multikinase inhibitors for more than a decade. However, drug resistance can severely restrict the efficacy of these drugs. Using CRISPR/CAS9 genome library screening, we evaluated Kelch-like ECH-associated protein 1 (KEAP1) as a key regulator of sorafenib’s susceptibility in HCC. We also investigated whether KEAP1’s knockdown can stabilize nuclear factor (erythroid-derived 2)-like 2 (NRF2) protein levels that led to sorafenib’s resistance, including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo. Furthermore, we clarified that fibroblast growth factor 21 (FGF21) is an important downstream regulator of NRF2 in HCC. Intriguingly, we observed that FGF21 bound to NRF2 through the C-terminus of FGF21, thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC. These findings, therefore, propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  • Badman, M.K., Pissios, P., Kennedy, A.R., Koukos, G., Flier, J.S., and Maratos-Flier, E. (2007). Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5, 426–437.

    Article  CAS  PubMed  Google Scholar 

  • Bruix, J., Qin, S., Merle, P., Granito, A., Huang, Y.H., Bodoky, G., Pracht, M., Yokosuka, O., Rosmorduc, O., Breder, V., et al. (2017). Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66.

    Article  CAS  PubMed  Google Scholar 

  • Bruix, J., Reig, M., and Sherman, M. (2016). Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 150, 835–853.

    Article  PubMed  Google Scholar 

  • Chen, J., Jin, R., Zhao, J., Liu, J., Ying, H., Yan, H., Zhou, S., Liang, Y., Huang, D., Liang, X., et al. (2015). Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett 367, 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J., Yu, Y., Ji, T., Ma, R., Chen, M., Li, G., Li, F., Ding, Q., Kang, Q., Huang, D., et al. (2016). Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma. Cancer Med 5, 2678–2687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, Y., and Zhang, Y. (2018). Application of the CRISPR/Cas9 system to drug resistance in breast cancer. Adv Sci 5, 1700964.

    Article  Google Scholar 

  • Chowdhury, I., Mo, Y., Gao, L., Kazi, A., Fisher, A.B., and Feinstein, S.I. (2009). Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element. Free Radic Biol Med 46, 146–153.

    Article  CAS  PubMed  Google Scholar 

  • Coskun, T., Bina, H.A., Schneider, M.A., Dunbar, J.D., Hu, C.C., Chen, Y., Moller, D.E., and Kharitonenkov, A. (2008). Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027.

    Article  CAS  PubMed  Google Scholar 

  • Dodson, M., Castro-Portuguez, R., and Zhang, D.D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23, 101107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Finn, R.S., Qin, S., Ikeda, M., Galle, P.R., Ducreux, M., Kim, T.Y., Kudo, M., Breder, V., Merle, P., Kaseb, A.O., et al. (2020). Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382, 1894–1905.

    Article  CAS  PubMed  Google Scholar 

  • Fisher, F.M., and Maratos-Flier, E. (2016). Understanding the physiology of FGF21. Annu Rev Physiol 78, 223–241.

    Article  CAS  PubMed  Google Scholar 

  • Gao, L., Wang, X., Tang, Y., Huang, S., Hu, C.A.A., and Teng, Y. (2017). FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res 36, 8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Geng, L., Lam, K.S.L., and Xu, A. (2020). The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol 16, 654–667.

    Article  CAS  PubMed  Google Scholar 

  • Hayes, J.D., and Dinkova-Kostova, A.T. (2014). The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39, 199–218.

    Article  CAS  PubMed  Google Scholar 

  • Housden, B.E., and Perrimon, N. (2016). Comparing CRISPR and RNAi-based screening technologies. Nat Biotechnol 34, 621–623.

    Article  CAS  PubMed  Google Scholar 

  • Huang, H.C., Nguyen, T., and Pickett, C.B. (2000). Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA 97, 12475–12480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huppke, P., Weissbach, S., Church, J.A., Schnur, R., Krusen, M., Dreha-Kulaczewski, S., Kühn-Velten, W.N., Wolf, A., Huppke, B., Millan, F., et al. (2017). Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat Commun 8, 818.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jackson, A.L., and Linsley, P.S. (2010). Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov 9, 57–67.

    Article  CAS  PubMed  Google Scholar 

  • Ji, L., Lin, Z., Wan, Z., Xia, S., Jiang, S., Cen, D., Cai, L., Xu, J., and Cai, X. (2020). miR-486–3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR. Cell Death Dis 11, 250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jimenez, T., Barrios, A., Tucker, A., Collazo, J., Arias, N., Fazel, S., Baker, M., Halim, M., Huynh, T., Singh, R., et al. (2020). DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer. Am J Cancer Res 10, 3487–3506.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, B.R., Lee, G.Y., Yu, H., Maeng, H.J., Oh, T.J., Kim, K.M., Moon, J. H., Lim, S., Jang, H.C., and Choi, S.H. (2018). Suppression of Nrf2 attenuates adipogenesis and decreases FGF21 expression through PPAR gamma in 3T3-L1 cells. Biochem Biophys Res Commun 497, 1149–1153.

    Article  CAS  PubMed  Google Scholar 

  • Kubo, E., Chhunchha, B., Singh, P., Sasaki, H., and Singh, D.P. (2017). Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress. Sci Rep 7, 14130.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee, D., Xu, I.M.J., Chiu, D.K.C., Leibold, J., Tse, A.P.W., Bao, M.H.R., Yuen, V.W.H., Chan, C.Y.K., Lai, R.K.H., Chin, D.W.C., et al. (2019). Induction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma. Hepatology 69, 1768–1786.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H., Park, B.C., Soon Kang, J., Cheon, Y., Lee, S., and Jae Maeng, P. (2020). MAM domain containing 2 is a potential breast cancer biomarker that exhibits tumour-suppressive activity. Cell Prolif 53, e12883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, D., and Li, Y. (2020). The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Target Ther 5, 108.

    Article  PubMed  PubMed Central  Google Scholar 

  • Li, W., Xu, H., Xiao, T., Cong, L., Love, M.I., Zhang, F., Irizarry, R.A., Liu, J.S., Brown, M., and Liu, X.S. (2014). MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol 15, 554.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin, Z., Xia, S., Liang, Y., Ji, L., Pan, Y., Jiang, S., Wan, Z., Tao, L., Chen, J., Lin, C., et al. (2020). LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription. Theranostics 10, 8834–8850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, J., Song, T., Zhou, W., Xing, L., Wang, S., Ho, M., Peng, Z., Tai, Y.T., Hideshima, T., Anderson, K.C., et al. (2019). A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity. Leukemia 33, 171–180.

    Article  PubMed  Google Scholar 

  • Llovet, J.M., Montal, R., Sia, D., and Finn, R.S. (2018). Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 15, 599–616.

    Article  PubMed  Google Scholar 

  • Llovet, J.M., Montal, R., and Villanueva, A. (2019). Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J Hepatol 70, 1262–1277.

    Article  PubMed  Google Scholar 

  • Marrero, J.A., Kulik, L.M., Sirlin, C.B., Zhu, A.X., Finn, R.S., Abecassis, M.M., Roberts, L.R., and Heimbach, J.K. (2018). Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 68, 723–750.

    Article  PubMed  Google Scholar 

  • Ouyang, Q., Liu, Y., Tan, J., Li, J., Yang, D., Zeng, F., Huang, W., Kong, Y., Liu, Z., Zhou, H., et al. (2019). Loss of ZNF587B and SULF1 contributed to cisplatin resistance in ovarian cancer cell lines based on Genome-scale CRISPR/Cas9 screening. Am J Cancer Res 9, 988–998.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., and Cuadrado, A. (2019). Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev 2019, 1–20.

    Article  Google Scholar 

  • Rojo de la Vega, M., Chapman, E., and Zhang, D.D. (2018). NRF2 and the hallmarks of cancer. Cancer Cell 34, 21–43.

    Article  CAS  PubMed  Google Scholar 

  • Rudalska, R., Dauch, D., Longerich, T., McJunkin, K., Wuestefeld, T., Kang, T.W., Hohmeyer, A., Pesic, M., Leibold, J., von Thun, A., et al. (2014). In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 20, 1138–1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saber, A., Liu, B., Ebrahimi, P., and Haisma, H.J. (2020). CRISPR/Cas9 for overcoming drug resistance in solid tumors. Daru 28, 295–304.

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Rivera, F.J., and Jacks, T. (2015). Applications of the CRISPR-Cas9 system in cancer biology. Nat Rev Cancer 15, 387–393.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sanghvi, V.R., Leibold, J., Mina, M., Mohan, P., Berishaj, M., Li, Z., Miele, M.M., Lailler, N., Zhao, C., de Stanchina, E., et al. (2019). The oncogenic action of NRF2 depends on de-glycation by fructosamine-3-kinase. Cell 178, 807–819.e21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shalem, O., Sanjana, N.E., Hartenian, E., Shi, X., Scott, D.A., Mikkelsen, T.S., Heckl, D., Ebert, B.L., Root, D.E., Doench, J.G., et al. (2014). Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343, 84–87.

    Article  CAS  PubMed  Google Scholar 

  • Singh, A., Venkannagari, S., Oh, K.H., Zhang, Y.Q., Rohde, J.M., Liu, L., Nimmagadda, S., Sudini, K., Brimacombe, K.R., Gajghate, S., et al. (2016). Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem Biol 11, 3214–3225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, C.Q., Li, Y., Mou, H., Moore, J., Park, A., Pomyen, Y., Hough, S., Kennedy, Z., Fischer, A., Yin, H., et al. (2017). Genome-wide CRISPR screen identifies regulators of mitogen-activated protein kinase as suppressors of liver tumors in mice. Gastroenterology 152, 1161–1173.e1.

    Article  CAS  PubMed  Google Scholar 

  • Sun, X., Niu, X., Chen, R., He, W., Chen, D., Kang, R., and Tang, D. (2016a). Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64, 488–500.

    Article  CAS  PubMed  Google Scholar 

  • Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., and Tang, D. (2016b). Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63, 173–184.

    Article  CAS  PubMed  Google Scholar 

  • Teng, Y., Zhao, H., Gao, L., Zhang, W., Shull, A.Y., and Shay, C. (2017). FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4-GSK3β-Nrf2 signaling. Cancer Res 77, 6215–6225.

    Article  CAS  PubMed  Google Scholar 

  • Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., and Jemal, A. (2015). Global cancer statistics, 2012. CA Cancer J Clin 65, 87–108.

    Article  PubMed  Google Scholar 

  • Wei, L., Lee, D., Law, C.T., Zhang, M.S., Shen, J., Chin, D.W.C., Zhang, A., Tsang, F.H.C., Wong, C.L.S., Ng, I.O.L., et al. (2019). Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun 10, 4681.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu, A., Feng, B., Yu, J., Yan, L., Che, L., Zhuo, Y., Luo, Y., Yu, B., Wu, D., and Chen, D. (2021). Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis. Redox Biol 46, 102131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia, S., Pan, Y., Liang, Y., Xu, J., and Cai, X. (2020). The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. Ebiomedicine 51, 102610.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu, J., Ji, L., Liang, Y., Wan, Z., Zheng, W., Song, X., Gorshkov, K., Sun, Q., Lin, H., Zheng, X., et al. (2020a). CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther 5, 298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, J., Ji, L., Ruan, Y., Wan, Z., Lin, Z., Xia, S., Tao, L., Zheng, J., Cai, L., Wang, Y., et al. (2021). UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma. Signal Transduct Target Ther 6, 190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y.Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.C., Graham, M., et al. (2009). Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects. Am J Physiol Endocrinol Metab 297, E1105–E1114.

    Article  CAS  PubMed  Google Scholar 

  • Xu, J., Wan, Z., Tang, M., Lin, Z., Jiang, S., Ji, L., Gorshkov, K., Mao, Q., Xia, S., Cen, D., et al. (2020b). N6-methyladenosine-modified circRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling. Mol Cancer 19, 163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto, M., Kensler, T.W., and Motohashi, H. (2018). The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 98, 1169–1203.

    Article  CAS  PubMed  Google Scholar 

  • Yau, T., Hsu, C., Kim, T.Y., Choo, S.P., Kang, Y.K., Hou, M.M., Numata, K., Yeo, W., Chopra, A., Ikeda, M., et al. (2019). Nivolumab in advanced hepatocellular carcinoma: sorafenib-experienced Asian cohort analysis. J Hepatol 71, 543–552.

    Article  CAS  PubMed  Google Scholar 

  • Yeh, W.L., Shioda, K., Coser, K.R., Rivizzigno, D., McSweeney, K.R., and Shioda, T. (2013). Fulvestrant-induced cell death and proteasomal degradation of estrogen receptor a protein in MCF-1 cells require the CSK c-Src tyrosine kinase. PLoS ONE 8, e60889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, Y., Bai, F., Liu, Y., Yang, Y., Yuan, Q., Zou, D., Qu, S., Tian, G., Song, L., Zhang, T., et al. (2015). Fibroblast growth factor (FGF21) protects mouse liver against D-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways. Mol Cell Biochem 403, 287–299.

    Article  CAS  PubMed  Google Scholar 

  • Yu, Y., He, J., Li, S., Song, L., Guo, X., Yao, W., Zou, D., Gao, X., Liu, Y., Bai, F., et al. (2016). Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway. Int Immunopharmacol 38, 144–152.

    Article  CAS  PubMed  Google Scholar 

  • Yu, Z., Lin, L., Jiang, Y., Chin, I., Wang, X., Li, X., Lo, E.H., and Wang, X. (2019). Recombinant FGF21 protects against blood-brain barrier leakage through Nrf2 upregulation in type 2 diabetes mice. Mol Neurobiol 56, 2314–2327.

    Article  CAS  PubMed  Google Scholar 

  • Yuan, Y., Li, H., Pu, W., Chen, L., Guo, D., Jiang, H., He, B., Qin, S., Wang, K., Li, N., et al. (2022). Cancer metabolism and tumor microenvironment: fostering each other? Sci China Life Sci 65, 236–279.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, B.C., Luo, B.Y., Zou, J.J., Wu, P.Y., Jiang, J.L., Le, J.Q., Zhao, R. R., Chen, L., and Shao, J.W. (2020). Co-delivery of sorafenib and CRISPR/Cas9 based on targeted core-shell hollow mesoporous organosilica nanoparticles for synergistic HCC therapy. ACS Appl Mater Interfaces 12, 57362–57312.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, C., Liu, Z., Bunker, E., Ramirez, A., Lee, S., Peng, Y., Tan, A.C., Eckhardt, S.G., Chapnick, D.A., and Liu, X. (2017). Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem 292, 15105–15120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, S., Yu, D., Wang, M., Huang, T., Wu, H., Zhang, Y., Zhang, T., Wang, W., Yin, J., Ren, G., et al. (2018). FGF21 attenuates pulmonary fibrogenesis through ameliorating oxidative stress in vivo and in vitro. Biomed Pharmacother 103, 1516–1525.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, A., Chevalier, N., Calderoni, M., Dubuis, G., Dormond, O., Ziros, P. G., Sykiotis, G.P., and Widmann, C. (2019). CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget 10, 7058–7070.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81702981, 81827804, 81902367, 81772546 and LQ18H160010), Zhejiang Provincial Natural Science Foundation of China (LY20H160021 and Y15H160052), China Postdoctoral Science Foundation (2020T130584 and 2020M671755), Health Innovation Talent Support Project of Zhejiang Medical and Health Science and Technology Plan (2021447581). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Yong Cang for giving comments and suggestions to this study. We also thank the Genome Center of WuXi AppTec Inc. for the initial data analysis of the CRISPR screening. We thank J. Iacona, Ph.D., from Liwen Bianji, Edanz Editing China (https://www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Jiang Chen, Shi Jiang, Huijiang Shao, Tong Ji, Jiayan He, Jie Zhao, Liuxin Cai, Xiao Liang, Junjie Xu & Xiujun Cai

  2. Key Laboratory of Laparoscopic Technology of Zhejiang Province, Hangzhou, 310016, China

    Jiang Chen, Shi Jiang, Tong Ji, Jiayan He, Jie Zhao, Liuxin Cai, Xiao Liang, Junjie Xu & Xiujun Cai

  3. Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, 310016, China

    Jiang Chen, Shi Jiang, Tong Ji, Jiayan He, Jie Zhao, Liuxin Cai, Xiao Liang, Junjie Xu & Xiujun Cai

  4. Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China

    Jiang Chen, Shi Jiang, Tong Ji, Jiayan He, Jie Zhao, Liuxin Cai, Xiao Liang, Junjie Xu & Xiujun Cai

  5. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Jiang Chen, Shi Jiang, Tong Ji, Jiayan He, Jie Zhao, Liuxin Cai, Xiao Liang, Junjie Xu & Xiujun Cai

  6. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Jiang Chen & Daniel Staiculescu

  7. Department of Hepatobiliary and Pancreatic Surgery, Shaoxing People’s Hospital, Shaoxing, 312000, China

    Huijiang Shao

  8. Department of Hematology, Ningbo First Hospital, Zhejiang University, Ningbo, 315010, China

    Bixia Li

Authors
  1. Jiang Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Shi Jiang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Huijiang Shao
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Bixia Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Tong Ji
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Daniel Staiculescu
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Jiayan He
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Jie Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Liuxin Cai
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Xiao Liang
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Junjie Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Xiujun Cai
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Junjie Xu or Xiujun Cai.

Ethics declarations

Compliance and ethics The author(s) declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Jiang, S., Shao, H. et al. CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway. Sci. China Life Sci. 65, 1998–2016 (2022). https://doi.org/10.1007/s11427-021-2067-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-021-2067-7

Keywords