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Published on: September 12, 2019
Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC
Yau-Tuen Chan1, Junyu Wu1, Yuanjun Lu1
1School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Background And Aims:
Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC.
Materials And Methods:
A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array.
Results:
CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC.
Conclusion:
Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.
Insights
Researchers identified Linc01056 as a key regulator of sorafenib response in hepatocellular carcinoma (HCC). Lower Linc01056 levels promote resistance by altering cell metabolism, suggesting it as a therapeutic target for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Sorafenib is a primary treatment for advanced hepatocellular carcinoma (HCC).
- Acquired resistance significantly limits sorafenib's clinical effectiveness in HCC patients.
- Identifying mechanisms of resistance is crucial for improving HCC therapy.
Purpose of the Study:
- To identify key long non-coding RNAs (lncRNAs) regulating sorafenib response in HCC.
- To elucidate the role and mechanism of Linc01056 in sorafenib resistance.
- To evaluate the clinical significance of Linc01056 in HCC patients.
Main Methods:
- Utilized CRISPR/Cas9 pooled lncRNA library screening to identify key lncRNAs.
- Investigated the function of Linc01056 in HCC cells in vitro and in vivo.
- Performed proteomic analysis to understand the underlying molecular mechanisms.
- Assessed clinical relevance using multiplex immunostaining on HCC microtissue arrays.
Main Results:
- Linc01056 was found to be downregulated in sorafenib-resistant HCC cells.
- Linc01056 knockdown decreased sorafenib sensitivity, suppressed apoptosis, and promoted tumor growth.
- Linc01056 regulates a metabolic switch from glycolysis to fatty acid oxidation (FAO) via PPARα.
- Inhibition of FAO or PPARα restored sorafenib sensitivity.
- Clinical analysis showed Linc01056 expression predicts better survival and sorafenib response in HCC patients.
Conclusions:
- Linc01056 acts as a critical epigenetic regulator of sorafenib response in HCC.
- Linc01056 is a potential therapeutic target for overcoming sorafenib resistance in HCC.
- Linc01056 expression levels correlate with metabolic status and patient outcomes in HCC.
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