PDCD2 sensitizes HepG2 cells to sorafenib by suppressing epithelial‑mesenchymal transition

Liu, Hongyu; Wang, Min; Liang, Na; Guan, Lina

doi:10.3892/mmr.2019.9860

Cited by 12 publications

(17 citation statements)

References 34 publications

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“…However, most patients eventually progressed to drug resistance diseases. Currently, the mechanisms involved in sorafenib resistance include activation of EGFR, c-Jun and/or AKT, microenvironmental hypoxia, epithelial-mesenchymal transition (EMT), activation of CSCs, resistance to apoptosis, cell cycle dysregulation, autophagy, and the abnormal expression of miRNAs and lncRNAs [36,[41][42][43][44][45][46][47][48]. A variety of miRNAs have been reported to be involved in sorafenib resistant in HCC (Table 1).…”

Section: Mirnas and Resistance To Sorafenibmentioning

confidence: 99%

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

et al. 2019

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Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumorspecific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

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Section: Mirnas and Resistance To Sorafenibmentioning

confidence: 99%

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

et al. 2019

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“…Currently, the most effective drug to control the development and progression of HCC is sorafenib [ 1 ]. Unfortunately, sorafenib resistance rate is relatively high and there is little study to explore the therapeutic resistance underlying sorafenib treatment [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: LATS2 overexpression attenuates the therapeutic resistance of liver cancer HepG2 cells to sorafenib-mediated death via inhibiting the AMPK–Mfn2 signaling pathway

Liu

Zhao

et al. 2019

Cancer Cell Int

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Background: Effective therapy for hepatocellular carcinoma (HCC) is currently an imperative issue, and sorafenib is a first-line drug for the treatment of HCC. However, the clinical benefit of sorafenib is often impaired by drug resistance. Accordingly, the present study was conducted to investigate the molecular mechanisms involving sorafenib resistance, with a focus on large tumor suppressor 2 (LATS2) and mitophagy.Methods: HepG2 liver cancer cells were treated with sorafenib and infected with adenovirus-loaded LATS2 (Ad-LATS2). Cell death, proliferation and migration were measured via western blotting analysis, immunofluorescence and qPCR. Mitochondrial function and mitophagy were determined via western blotting and immunofluorescence.Results: Our data indicated that LATS2 expression was repressed by sorafenib treatment, and overexpression of LATS2 could further enhance sorafenib-mediated apoptosis in HepG2 liver cancer cells. At the molecular level, mitochondrial stress was triggered by sorafenib treatment, as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS production, more cyc-c release into the nucleus, and elevated mitochondrial proapoptotic proteins. However, in response to mitochondrial damage, mitophagy was activated by sorafenib treatment, whereas LATS2 overexpression effectively inhibited mitophagy activity and thus augmented sorafenib-mediated mitochondrial stress. Subsequently, we also demonstrated that the AMPK-MFN2 signaling pathway was involved in mitophagy regulation after exposure to sorafenib treatment and/or LATS2 overexpression. Inhibition of the AMPK pathway interrupted mitophagy and thus enhanced the antitumor property of sorafenib, similar to the results obtained via overexpression of LATS2. Conclusions:Altogether, our findings revealed the importance of the LATS2/AMPK/MFN2/mitophagy axis in understanding sorafenib resistance mechanisms, with a potential application to increase the sensitivity response of sorafenib in the treatment of liver cancer.

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“…In HCC, long-term exposure of liver cancer cells to sorafenib can induce epithelial-mesenchymal transition to develop resistance, increase the risk of invasive and rebound growth (24). PDCD2 sensitizes HepG2 cells to sorafenib by inhibiting mesenchymal transformation of epithelial cells (25). Therefore, we hypothesized that knockdown of H19 would sensitize HCC cells to sorafenib via EMT.…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA H19 is involved in sorafenib resistance in hepatocellular carcinoma by upregulating miR‑675

Liu

et al. 2020

Oncol Rep

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Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). Since many HCC patients experience drug resistance, there is an urgent need to discover more effective therapeutic strategies to overcome drug resistance. Long non-coding RNAs (lncRNAs) play an important role in tumor drug resistance. However, research on the role of lncRNA H19 in sorafenib resistance in HCC is quite limited. In the present study, CCK-8 assay, RT-qPCR, EdU staining, immunofluorescence staining, and western blot analysis were used to detect the effect of lncRNA H19 on sorafenib resistance of HCC cells. H19 expression was found to be negatively related to sorafenib sensitivity in HCC cells. Knockdown of lncRNA H19 elevated sorafenib sensitivity by suppressing epithelial-mesenchymal transition (EMT) in HCC cells. H19 upregulated miR-675 expression. miR-675 inhibitor decreased the cell viability in sorafenib-treated HCC cells, while miR-675 overexpression had the opposite effect on the treated cells. When the cells were pretreated with miR-675 mimic, H19 siRNA did not alter the effect of miR-675 on sorafenib sensitivity. In conclusion, our study provides new clues for further clinical treatment of sorafenib-resistant liver cancer patients.

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PDCD2 sensitizes HepG2 cells to sorafenib by suppressing epithelial‑mesenchymal transition

Cited by 12 publications

References 34 publications

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

RETRACTED ARTICLE: LATS2 overexpression attenuates the therapeutic resistance of liver cancer HepG2 cells to sorafenib-mediated death via inhibiting the AMPK–Mfn2 signaling pathway

Long non‑coding RNA H19 is involved in sorafenib resistance in hepatocellular carcinoma by upregulating miR‑675

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