Abstract
Acquired resistance to cisplatin (DDP)-based chemotherapy greatly hinders the treatment of gastric cancer (GC). LINC00665 serves as an oncogene in GC. Hence, the current study was designed to investigate the regulatory effects of LINC00665 on DDP-resistance of GC. LINC00665 and miR-379-5p expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Glucose regulated protein 78 (GRP78) protein level was measured by western blot assay. Interactions between LINC00665 and miR-379-5p or between miR-379-5p and GRP78 were verified by dual luciferase reporter assay. Cell counting kit 8 (CCK-8) assay and flow cytometry assay respectively determine the proliferative ability and apoptosis of GC cells. Western blot analysis was also performed to detect the protein levels of C/EBP-homologous protein (CHOP), X box binding protein (XBP1) and apoptosis-related proteins. In addition, GRP78 expression was evaluated by immunofluorescence. It was observed that the expression levels of LINC00665 and GRP78 were upregulated, and the expression level of miR-379-5p was downregulated in DDP-sensitive and DDP-resistant GC cell lines. What’s more, GRP78 expression and the cell growth inhibition rates of DDP-sensitive and DDP-resistant GC cells had a negative correlation. Additionally, miR-379-5p was a target miRNA of LINC00665, and GRP78 was a target mRNA of miR-379-5p. Functional studies revealed that knockdown of LINC00665 inhibited DDP-resistant GC cell proliferation, induced apoptosis as well as suppressed Endoplasmic reticulum (ER) stress. Mechanistically, knockdown of LINC00665 downregulated GRP78 expression by strengthening miR-379-5p. LINC00665 silencing could overcome DPP-resistance of GC cells by downregulating GRP78 via sponging miR-379-5p, indicating that LINC00665 might be a potential therapeutic target for DDP- resistant GC patients.
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The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.
References
Casamayor M, Morlock R, Maeda H, Ajani J (2018) Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience 12:883. https://doi.org/10.3332/ecancer.2018.883
Chen W, Yu Z, Huang W, Yang Y, Wang F, Huang H (2020) LncRNA LINC00665 promotes prostate cancer progression via miR-1224-5p/SND1 axis. Onco Targets Ther 13:2527–2535. https://doi.org/10.2147/OTT.S241578
Feng H, Liu X (2020) Interaction between ACOT7 and LncRNA NMRAL2P via methylation regulates gastric cancer progression. Yonsei Med J 61:471–481. https://doi.org/10.3349/ymj.2020.61.6.471
Hetz C, Zhang K, Kaufman RJ (2020) Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. https://doi.org/10.1038/s41580-020-0250-z
King AP, Wilson JJ (2020) Endoplasmic reticulum stress: an arising target for metal-based anticancer agents. Chem Soc Rev. https://doi.org/10.1039/d0cs00259c
Li Z, Li Z (2012) Glucose regulated protein 78: a critical link between tumor microenvironment and cancer hallmarks. Biochim Biophys Acta 1826:13–22. https://doi.org/10.1016/j.bbcan.2012.02.001
Liu X, Lu X, Zhen F, Jin S, Yu T, Zhu Q, Wang W, Xu K, Yao J, Guo R (2019) LINC00665 induces acquired resistance to Gefitinib through recruiting EZH2 and activating PI3K/AKT pathway in NSCLC. Mol Ther Nucleic Acids 16:155–161. https://doi.org/10.1016/j.omtn.2019.02.010
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Machihara K, Namba T (2020) Kuanoniamine C stimulates bortezomib-induced cell death via suppression of glucose-regulated protein 78 in osteosarcoma. Biochem Biophys Res Commun 527:289–296. https://doi.org/10.1016/j.bbrc.2020.04.109
Qi H, Xiao Z, Wang Y (2019) Long non-coding RNA LINC00665 gastric cancer tumorigenesis by regulation miR-149-3p/RNF2 axis. Onco Targets Ther 12:6981–6990. https://doi.org/10.2147/OTT.S214588
Ran D, Mao J, Shen Q, Xie C, Zhan C, Wang R, Lu W (2017) GRP78 enabled micelle-based glioma targeted drug delivery. J Control Release 255:120–131. https://doi.org/10.1016/j.jconrel.2017.03.037
Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S (2017) Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 8:CD004064. https://doi.org/10.1002/14651858.CD004064.pub4
Wang D, Zhang P, Xu X, Wang J, Wang D, Peng P, Zheng C, Meng QJ, Yang L, Luo Z (2019a) Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy. Cell Death Dis 10:887. https://doi.org/10.1038/s41419-019-2125-9
Wang G, Yang B, Fu Z, Wang X, Zhang Z (2019b) Efficacy and safety of oxaliplatin-based regimen versus cisplatin-based regimen in the treatment of gastric cancer: a meta-analysis of randomized controlled trials. Int J Clin Oncol 24:614–623. https://doi.org/10.1007/s10147-019-01425-x
Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M (2020) Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer 19:62. https://doi.org/10.1186/s12943-020-01185-7
Wu D, Niu X, Tao J, Li P, Lu Q, Xu A, Chen W, Wang Z (2017) MicroRNA-379-5p plays a tumor-suppressive role in human bladder cancer growth and metastasis by directly targeting MDM2. Oncol Rep 37:3502–3508. https://doi.org/10.3892/or.2017.5607
Wu SR, Wu Q, Shi YQ (2020) Recent advances of miRNAs in the development and clinical application of gastric cancer. Chin Med J (Engl). https://doi.org/10.1097/CM9.0000000000000921
Xu X, Wang Y, Mojumdar K, Zhou Z, Jeong KJ, Mangala LS, Yu S, Tsang YH, Rodriguez-Aguayo C, Lu Y, Lopez-Berestein G, Sood AK, Mills GB, Liang H (2019) A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis. J Clin Invest 129:5343–5356. https://doi.org/10.1172/JCI123396
Yang B, Bai Q, Chen H, Su K, Gao C (2020) LINC00665 induces gastric cancer progression through activating Wnt signaling pathway. J Cell Biochem 121:2268–2276. https://doi.org/10.1002/jcb.29449
Yuan L, Xu ZY, Ruan SM, Mo S, Qin JJ, Cheng XD (2020) Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance. Mol Cancer 19:96. https://doi.org/10.1186/s12943-020-01219-0
Zhang F, Duan C, Yin S, Tian Y (2020) MicroRNA-379-5p/YBX1 axis regulates cellular EMT to suppress migration and invasion of nasopharyngeal carcinoma cells. Cancer Manag Res 12:4335–4346. https://doi.org/10.2147/CMAR.S253504
Zheng Z, Shang Y, Tao J, Zhang J, Sha B (2019) Endoplasmic reticulum stress signaling pathways: activation and diseases. Curr Protein Pept Sci 20:935–943. https://doi.org/10.2174/1389203720666190621103145
Zhu Y, Xie M, Meng Z, Leung LK, Chan FL, Hu X, Chi K, Liu C, Yao X (2019) Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells. Oncogene 38:5778–5791. https://doi.org/10.1038/s41388-019-0846-y
Zuo Y, Zheng W, Liu J, Tang Q, Wang SS, Yang XS (2020) MiR-34a-5p/PD-L1 axis regulates cisplatin chemoresistance of ovarian cancer cells. Neoplasma 67:93–101. https://doi.org/10.4149/neo_2019_190202N106
Funding
This work was supported by Jiangsu Provincial Natural Science Fund (No. BK20151017), Six Major Talent Peak Project of Jiangsu Province (No. WSW-050), Natural Science Foundation of China (No. 81502052), Youth Talent Program of Jiangsu Cancer Hospital (No. QL 201816), Jiangsu Provincial Medical Youth Talent (No.QNRC2016651), The TalentProgram of Jiangsu Cancer Hospital, 333 High-Level Talent Training Project in Jiangsu Province (No. LGY2018069).
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Yue, C., Yu, C., Peng, R. et al. LINC00665/miR-379-5p/GRP78 regulates cisplatin sensitivity in gastric cancer by modulating endoplasmic reticulum stress. Cytotechnology 73, 413–422 (2021). https://doi.org/10.1007/s10616-021-00466-3
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DOI: https://doi.org/10.1007/s10616-021-00466-3