HOTAIR Competitively Binds MiRNA330 as a Molecular Sponge to Increase the Resistance of Gastric Cancer to Trastuzumab

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Author(s): Liangyu Bie, Suxia Luo*, Dan Li, Yan Wei, Yu Mu, Xiaobing Chen, Saiqi Wang, Ping Guo, Xiaoyu Lu.

Journal Name: Current Cancer Drug Targets

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Background: HOTAIR, one of the most widely studied long non-coding RNAs in tumors, is closely related to tumor proliferation, migration, invasion and chemoresistance.

Objective: Here, we studied the mechanism behind proliferation and chemoresistance processes.

Methods: A total of 75 samples were collected from patients who underwent surgical resection of their gastric cancer and received trastuzumab treatment. Primary cells were isolated and cultured. We also developed a cell line overexpressing HOTAIR by constructing a lentiviral vector. These cell lines were studied using an array of established biomolecular methods.

Results: We found that HOTAIR levels were inversely associated with sensitivity to trastuzumab in gastric cancer, and that overexpression of HOTAIR can promote the proliferation and invasion of gastric cancer cells. The sensitivity of cells overexpressing HOTAIR to two different types of human epidermal growth factor receptor 2 (HER2) inhibitors (trastuzumab and afatinib) showed that overexpression of HOTAIR is specific for trastuzumab resistance. Furthermore, luciferase reporter gene assay and western blot assay showed that there is a HOTAIR-miRNA330-ERBB4 competitive endogenous RNA regulatory network with miRNA330 as the core.

Conclusion: HOTAIR can not only promote tumor proliferation, but also enhances the resistance of tumor cells to drugs. Our experimental data not only showed strong expression of HOTAIR in gastric cancer, but also that strong expression of HOTAIR caused the sensitivity of gastric cancer cells to trastuzumab, which is a useful reference for postoperative medication.

Keywords: Trastuzumab, HOTAIR, Afatinib, ERBB4, HER2, miRNA330, Gastric Cancers

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(E-pub Ahead of Print)
DOI: 10.2174/1568009620666200504114000
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