The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

Tang, Weiwei; Chen, Ziyi; Zhang, Wenling; Cheng, Yufeng; Zhang, Betty; Wu, Fan; Wang, Qian; Wang, Shouju; Ding, Rong; Reiter, Florian P.; Toni, Enrico N. De; Wang, Xuehao

doi:10.1038/s41392-020-0187-x

Cited by 641 publications

(460 citation statements)

References 164 publications

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“…The tumor tissues were then cut into 2-3 mm 3 pieces and subcutaneously implanted into the flanks of NOD/SCID mice. The tissues from mice bearing PDX tumors were harvested and cut into pieces when the tumor volume reached 1-2 cm 3 , and then implanted into BALB/c nude mice. When the xenografted tumors grew to 50 mm 3 , recombinant lentivirus vectors were intratumorally injected into the tumor tissues for 20 days.…”

Section: Western Blottingmentioning

confidence: 99%

“…1,2 Despite the tremendous progress in HCC treatment, therapeutic options remain limited. 3,4 Only a small proportion of patients with HCC are eligible for curative treatments such as surgical resection, ablation, and liver transplantation. The majority of patients with HCC demonstrate postsurgical recurrence and metastasis, resulting in a poor 5-year overall survival rate.…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

Zhang

et al. 2021

Sig Transduct Target Ther

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236

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N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.

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Section: Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

Zhang

et al. 2021

Sig Transduct Target Ther

Self Cite

236

161

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“…Sorafenib is a multiple-target tyrosine kinase inhibitor (TKI) and can inhibit Raf-1, B-Raf, and kinase activity in the Ras/Raf/MEK/ERK signaling pathways, to further suppress tumor cell proliferation. The mechanism of drug resistance development may be related to changes in epigenetics in drug targets, upregulated transport processes, regulated cell death, or the tumor microenvironment [ 227 ]. The patient response rate of sorafenib is poor (0.7–3.0%); however, it is the recommend standard treatment for advanced HCC [ 228 ].…”

Section: The Stemness Of Hcc Contributes To the Limitation Of Targmentioning

confidence: 99%

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

Ngo

Jeng

Kuo

et al. 2021

IJMS

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Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.

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“…Sorafenib targeting multiple receptor tyrosine kinases (RTKs) is currently an effective first-line therapy for HCC. However, sorafenib resistance is frequently observed during HCC treatment [134]. The lncRNA TUC338 has been known to be involved in the development of HCC and sorafenib resistance [135].…”

Section: Clinical Application Of Lncrnas and Circrnas As Novel Biomarmentioning

confidence: 99%

Epigenetic Associations between lncRNA/circRNA and miRNA in Hepatocellular Carcinoma

Han

Hur

Cho

et al. 2020

Cancers

131

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The three major members of non-coding RNAs (ncRNAs), named microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in hepatocellular carcinoma (HCC) development. Recently, the competing endogenous RNA (ceRNA) regulation model described lncRNA/circRNA as a sponge for miRNAs to indirectly regulate miRNA downstream target genes. Accumulating evidence has indicated that ceRNA regulatory networks are associated with biological processes in HCC, including cancer cell growth, epithelial to mesenchymal transition (EMT), metastasis, and chemoresistance. In this review, we summarize recent discoveries, which are specific ceRNA regulatory networks (lncRNA/circRNA-miRNA-mRNA) in HCC and discuss their clinical significance.

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The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

Cited by 641 publications

References 164 publications

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

Epigenetic Associations between lncRNA/circRNA and miRNA in Hepatocellular Carcinoma

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