Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance

Xiang, Di; Sun, Wen; Zhou, Tengfei; Zhang, Cheng; Cheng, Zhuo; Li, Shichao; Jiang, Weiqi; Wang, Ruoyu; Fu, Gongbo; Cui, Xiuliang; Hou, Guoqing; Jin, Guang‐Zhi; Li, Hengyu; Hou, Cai-Ying; Liu, Hui; Wang, Hongyang; Ding, Jin

doi:10.1136/gutjnl-2018-317440

Cited by 90 publications

(70 citation statements)

References 34 publications

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“…Various numbers of Huh7/HepG2 miR-361-3p mimic or miR-361-3p sponge and their control cells were digested and seeded into 96-well ultra-low attachment (2,4,8,16,32, 64 cells per well, n = 8) and cultured in DMEM/F12 (Gibco) supplemented with 1% FBS, 20 ng/mL bFGF and 20 ng/mL EGF for seven days.…”

Section: In Vitro Limiting Dilution Assaymentioning

confidence: 99%

“…T-ICs or CSCs were rst discovered in blood system diseases (6). Later studies also con rmed the existence of T-ICs or CSCs in solid tumors, including breast cancer, liver cancer and glioma (7)(8)(9). Currently researches suggest that T-ICs or CSCs are responsible for the progression, metastasis, recurrence and chemo-resistance of cancers (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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miR-361-3p Regulates Liver Tumor-initiating Cells Expansion and Chemo-resistance

Zhang

Fan

et al. 2020

Preprint

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Background: Increasing evidence shows that liver tumor-initiating cells (T-ICs) closely associated with the progression, metastasis, recurrence and chemo-resistance of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver T-ICs remains unclear. The purpose of our study was to explore the role of miR-361-3p in the expansion of liver T-ICs and the potential molecular mechanism.Results: Flow cytometry analysis was performed to isolate CD24+, CD133+ or EpCAM+ cells from primary HCC cells or HCC cell lines. Real-time PCR was used to detect the expression of miR-361-3p in liver T-ICs. The impact of miR-361-3p on liver T-ICS expansion was investigated both in vivo and in vitro. The correlation between miR-361-3p expression and TACE (transcatheter arterial chemoembolization) or sorafenib benefits in HCC was evaluated in patient cohorts. miR-361-3p expression is upregulated in liver T-ICs. Knockdown of miR-361-3p impairs the self-renewal and tumorigenicity liver T-ICs. Conversely, forced miR-361-3p expression enhances the self-renewal and tumorigenicity liver T-ICs. Mechanistically, miR-361-3p directly targets SOX1 via binding its 3’-UTR in liver T-ICs. Moreover, miR-361-3p knockdown hepatoma cells are more sensitive to cisplatin or sorafenib treatment. Clinical cohort analysis demonstrates that miR-361-3p low HCC patients are benefited from TACE or sorafenib treatment. Conclusions: Our findings revealed the crucial role of the miR-361-3p in liver T-IC expansion and TACE or sorafenib response, rendering miR-361-3p an optimal target for the prevention and intervention in HCC.

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Section: In Vitro Limiting Dilution Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-361-3p Regulates Liver Tumor-initiating Cells Expansion and Chemo-resistance

Zhang

Fan

et al. 2020

Preprint

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“…The OC cells or OC patients' tissues were lysed with cell lysis buffer (Beyotime) followed by supersonic splitting as described previous (13). The total protein was quantified using a BCA Protein…”

Section: Western Blotting Assaysmentioning

confidence: 99%

Long non-coding RNA THOR promotes Ovarian Cancer cells progression via IL-6/STAT3 pathway

Ge¹,

Han²,

Shan³

et al. 2020

Preprint

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Background: Ovarian cancer (OC) is one of the most common malignant tumors in the world. The prognosis of OC remains poor due to the advanced stage and distant metastasis at the time of diagnosis. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in OC remains unclear. Methods: RT-PCR and western blot analysis were used to detect the expression of THOR, p-STAT3 and IL-6. The impact of THOR on OC proliferation, metastasis and self-renewal was investigated in vitro and in vivo. The prognostic value of THOR was determined in OC patient cohorts. Results: In this study, our results find that THOR is markedly upregulated in human OC tissues and predicts the poor prognosis of OC patients. Functional studies have revealed that knockdown of THOR inhibits the growth, metastasis and self-renewal of OC cells. Mechanistically, THOR drives OC cell progression via the IL-6/STAT3 signaling. Moreover, the specific STAT3 inhibitor S3I-201 or IL-6R inhibitor tocilizumab diminish the discrepancy in the growth, metastatic and self-renewal capacity between THOR-silenced OC cells and control cells, which further confirm that IL-6/STAT3 is required in THOR-driven OC cells progression. Conclusion: Our findings reveal that THOR could promote OC cells growth, metastasis and self-renewal by activating IL-6/STAT3 signaling and may be a good predictive factor and therapeutic target.

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“…Epithelialmesenchymal transition (EMT) and cancer stem cell (CSC) are typical tumor heterogeneity models and contribute to phenotypic diversity of HCC cells. Stemness and mesenchymal features contributing to primary sorafenib resistance might be acquired at tumor initiation with the help of oncofetal proteins or pathogenic factors [5,6]. Acquired resistance is always established during long-term sorafenib exposure, whereby genomic instability serves as a platform in which random mutations occur in different tumor cells subsequently endowed with different fitness, and sorafenib itself as a selective force favors the outgrowth of drug-resistant subclones.…”

Section: Introductionmentioning

confidence: 99%

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

et al. 2020

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A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

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Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance

Cited by 90 publications

References 34 publications

miR-361-3p Regulates Liver Tumor-initiating Cells Expansion and Chemo-resistance

miR-361-3p Regulates Liver Tumor-initiating Cells Expansion and Chemo-resistance

Long non-coding RNA THOR promotes Ovarian Cancer cells progression via IL-6/STAT3 pathway

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

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