Long non-coding RNA MACC1-AS1 mediates cisplatin resistance in gastric cancer through AKT/mTOR pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 NUERMAIMAITI·Yeerxun , BAI Jie

Department of Gastroenterology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, P. R. China;

Corresponding author：

NUERMAIMAITI·Yeerxun, Email: 867703953@qq.com

Keywords：

long non-coding RNA; metastasis-associated in colon cancer 1-antisense RNA; gastric cancer; drug resistance; apoptosis

DOI：

10.7507/1007-9424.202106074

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Objective To investigate the role of long non-coding RNA metastasis-associated in colon cancer 1-antisense RNA （MACC1-AS1）in cisplatin resistant gastric cancer and its possible mechanism. Methods Human gastric cancer cell line BGC823 and cisplatin resistant gastric cancer cell line (BGC823/DDP) were selected as the research objects. BGC823/DDP cells were transfected and divided into negative control group (si-NC group, transfected with si-NC empty plasmid) and MACC1-AS1 gene silencing group (si-MACC1-AS1 group, transfected with si-MACC1-AS1 plasmid). The BGC823 cells were transfected and divided into positive control group (pcDNA-NC group, transfected with pcDNA-NC empty plasmid) and MACC1-AS1 gene overexpression group (pcDNA-MACC1-AS1 group, transfected with pcDNA-MACC1-AS1 plasmid). MTT was used to detect the inhibition and 50% inhibition concentration (IC₅₀). Flow cytometry was used to detect apoptosis. Real-time fluorescence quantitative PCR was used to detect the mRNA expression levels of MACC1-AS1, B-lymphoma-2 gene (Bcl-2), Bcl-2 related X gene (Bax), mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), protein kinase B (AKT), and phosphorylated AKT (p-AKT). Western blot was used to detect the protein expression levels of Bax, Bcl-2, p-mTOR, mTOR, AKT, and p-AKT. Results The relative expression level of MACC1-AS1 mRNA in BGC823/DDP cells was higher than that in BGC823 gastric cancer cells (P<0.01). The relative expression level of MACC1-AS1 mRNA in the si-MACC1-AS1 group cells was lower than that in the si-NC group cells (P<0.01). The relative expression level of MACC1-AS1 mRNA in the pcDNA-MACC1-AS1 group cells was higher than that in the pcDNA-NC group cells (P<0.01). The cell growth inhibition rate and IC₅₀ of the si-MACC1-AS1 group were higher than those of the si-NC group (P<0.01). The cell growth inhibition rate and IC₅₀ of the pcDNA-MACC1-AS1 group were lower than those of the pcDNA-NC group (P<0.01). The mRNA and protein relative expression levels of Bcl-2, p-AKT/AKT and p-mTOR/mTOR in the pcDNA-MACC1-AS1 group were significantly higher than those in the pcDNA-NC group (P<0.01). The relative expression levels of Bax protein and mRNA in the pcDNA-MACC1-AS1 group were significantly lower than those in the pcDNA-NC group (P<0.01). The apoptosis rate of the pcDNA-MACC1-AS1 group was significantly lower than that of the pcDNA-NC group (P<0.01). The mRNA and protein relative expression levels of Bcl-2, p-AKT/AKT and p-mTOR/mTOR in the si-MACC1-AS1 group were significantly lower than those in the si-NC group (P<0.01). The relative expression levels of Bax protein and mRNA in the si-MACC1-AS1 group were significantly higher than those in the si-NC group (P<0.01). The apoptosis rate of the si-MACC1-AS1 group was significantly higher than that of the si-NC group (P<0.01). Conclusions MACC1-AS1 highly expresses in cisplatin resistant gastric cancer cells. Overexpression of MACC1-AS1 regulates AKT/mTOR pathway mediated apoptosis and enhances cisplatin resistance of gastric cancer cells.

Citation： NUERMAIMAITI·Yeerxun, BAI Jie. Long non-coding RNA MACC1-AS1 mediates cisplatin resistance in gastric cancer through AKT/mTOR pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(4): 458-464. doi: 10.7507/1007-9424.202106074 Copy

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2.	Wei L, Sun J, Zhang N, et al. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer, 2020, 19(1): 62. doi: 10.1186/s12943-020-01185-7.
3.	Deng W, Zhang Y, Cai J, et al. LncRNA-ANRIL promotes gastric cancer progression by enhancing NF-kB signaling. Exp Biol Med (Maywood), 2019, 244(12): 953-959.
4.	Choi RS, Lai WYX, Lee LTC, et al. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn, 2019, 19(10): 863-874.
5.	Mao W, Li T. LncRNA MACC1-AS1 promotes lung adenocarcinoma cell proliferation by downregulating PTEN. Cancer Biother Radiopharm, 2020, 35(4): 313-318.
6.	Tong H, Liu X, Li T, et al. MACC1-AS1 promotes hepatocellular carcinoma cell invasion and proliferation by regulating PAX8. Aging (Albany NY), 2020, 12(1): 70-79.
7.	Guo Y, Zhong J, Wu F, et al. Long noncoding RNA MACC1-AS1 promotes the stemness of hepatocellular carcinoma cells by antagonizing miR-145. J Int Med Res, 2020, 48(4): 300060520920411. doi: 10.1177/0300060520920411.
8.	He W, Liang B, Wang C, et al. MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer. Oncogene, 2019, 38(23): 4637-4654.
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10.	Chen S, Shen X. Long noncoding RNAs: functions and mechanisms in colon cancer. Mol Cancer, 2020, 19(1): 167. doi: 10.1186/s12943-020-01287-2.
11.	Braga EA, Fridman MV, Moscovtsev AA, et al. LncRNAs in ovarian cancer progression, metastasis, and main pathways: ceRNA and alternative mechanisms. Int J Mol Sci, 2020, 21(22): 8855. doi: 10.3390/ijms21228855.
12.	He J, Zhu S, Liang X, et al. LncRNA as a multifunctional regulator in cancer multi-drug resistance. Mol Biol Rep, 2021, 48(8): 1-15.
13.	Egranov SD, Hu Q, Lin C, et al. LncRNAs as tumor cell intrinsic factors that affect cancer immunotherapy. RNA Biol, 2020, 17(11): 1625-1627.
14.	Zhao Y, Liu Y, Lin L, et al. The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1. Mol Cancer, 2018, 17(1): 69. doi: 10.1186/s12943-018-0820-2.
15.	Zheng D, Che D, Lin F, et al. LncRNA MACC1-AS1/MACC1 enhances the progression of glioma via regulating metabolic plasticity. Cell Cycle, 2020, 19(18): 2286-2297.
16.	Xue W, Shen Z, Li L, et al. Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma. Mol Ther Nucleic Acids, 2021, 23: 592-602.
17.	Zhu L, Zhu Y, Han S, et al. Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis, 2019, 10(6): 383. doi: 10.1038/s41419-019-1585-2.
18.	Zhang F, Wang H, Yu J, et al. LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM. Mol Cancer, 2021, 20(1): 6. doi: 10.1186/s12943-020-01299-y.
19.	Dong H, Wang W, Chen R, et al. Exosome-mediated transfer of lncRNA-SNHG14 promotes trastuzumab chemoresistance in breast cancer. Int J Oncol, 2018, 53(3): 1013-1026.
20.	Zhang YF, Li CS, Zhou Y, et al. Propofol facilitates cisplatin sensitivity via lncRNA MALAT1/miR-30e/ATG5 axis through suppressing autophagy in gastric cancer. Life Sci, 2020, 244: 117280. doi: 10.1016/j.lfs.2020.117280.
21.	Xu Z, Han X, Ou D, et al. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl Microbiol Biotechnol, 2020, 104(2): 575-587.
22.	Deng J, Bai X, Feng X, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer, 2019, 19(1): 618. doi: 10.1186/s12885-019-5824-9.
23.	沈二栋, 翁洁, 文芳, 等. 衣霉素诱导的内质网应激对人食管癌细胞自噬和凋亡的影响及其与奥沙利铂化疗耐药的关系. 肿瘤药学, 2019, 9(1): 26-34.
24.	王昌高, 昝慧, 张万里, 等. 胡桃醌对胃癌细胞耐药性及细胞中ANXA2、ERCC1表达和AKT/mTOR信号通路的影响. 胃肠病学和肝病学杂志, 2020, 29(2): 136-141.
25.	Wu Q, Ma J, Wei J, et al. FOXD1-AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway. Mol Oncol, 2021, 15(1): 299-316.

1. 雷林, 彭绩. 2000-2019年中国胃癌流行病学趋势分析. 中华消化外科杂志, 2021, 20(1): 102-109.
2. Wei L, Sun J, Zhang N, et al. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer, 2020, 19(1): 62. doi: 10.1186/s12943-020-01185-7.
3. Deng W, Zhang Y, Cai J, et al. LncRNA-ANRIL promotes gastric cancer progression by enhancing NF-kB signaling. Exp Biol Med (Maywood), 2019, 244(12): 953-959.
4. Choi RS, Lai WYX, Lee LTC, et al. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn, 2019, 19(10): 863-874.
5. Mao W, Li T. LncRNA MACC1-AS1 promotes lung adenocarcinoma cell proliferation by downregulating PTEN. Cancer Biother Radiopharm, 2020, 35(4): 313-318.
6. Tong H, Liu X, Li T, et al. MACC1-AS1 promotes hepatocellular carcinoma cell invasion and proliferation by regulating PAX8. Aging (Albany NY), 2020, 12(1): 70-79.
7. Guo Y, Zhong J, Wu F, et al. Long noncoding RNA MACC1-AS1 promotes the stemness of hepatocellular carcinoma cells by antagonizing miR-145. J Int Med Res, 2020, 48(4): 300060520920411. doi: 10.1177/0300060520920411.
8. He W, Liang B, Wang C, et al. MSC-regulated lncRNA MACC1-AS1 promotes stemness and chemoresistance through fatty acid oxidation in gastric cancer. Oncogene, 2019, 38(23): 4637-4654.
9. Sexton RE, Al Hallak MN, Diab M, et al. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev, 2020, 39(4): 1179-1203.
10. Chen S, Shen X. Long noncoding RNAs: functions and mechanisms in colon cancer. Mol Cancer, 2020, 19(1): 167. doi: 10.1186/s12943-020-01287-2.
11. Braga EA, Fridman MV, Moscovtsev AA, et al. LncRNAs in ovarian cancer progression, metastasis, and main pathways: ceRNA and alternative mechanisms. Int J Mol Sci, 2020, 21(22): 8855. doi: 10.3390/ijms21228855.
12. He J, Zhu S, Liang X, et al. LncRNA as a multifunctional regulator in cancer multi-drug resistance. Mol Biol Rep, 2021, 48(8): 1-15.
13. Egranov SD, Hu Q, Lin C, et al. LncRNAs as tumor cell intrinsic factors that affect cancer immunotherapy. RNA Biol, 2020, 17(11): 1625-1627.
14. Zhao Y, Liu Y, Lin L, et al. The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1. Mol Cancer, 2018, 17(1): 69. doi: 10.1186/s12943-018-0820-2.
15. Zheng D, Che D, Lin F, et al. LncRNA MACC1-AS1/MACC1 enhances the progression of glioma via regulating metabolic plasticity. Cell Cycle, 2020, 19(18): 2286-2297.
16. Xue W, Shen Z, Li L, et al. Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma. Mol Ther Nucleic Acids, 2021, 23: 592-602.
17. Zhu L, Zhu Y, Han S, et al. Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis, 2019, 10(6): 383. doi: 10.1038/s41419-019-1585-2.
18. Zhang F, Wang H, Yu J, et al. LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM. Mol Cancer, 2021, 20(1): 6. doi: 10.1186/s12943-020-01299-y.
19. Dong H, Wang W, Chen R, et al. Exosome-mediated transfer of lncRNA-SNHG14 promotes trastuzumab chemoresistance in breast cancer. Int J Oncol, 2018, 53(3): 1013-1026.
20. Zhang YF, Li CS, Zhou Y, et al. Propofol facilitates cisplatin sensitivity via lncRNA MALAT1/miR-30e/ATG5 axis through suppressing autophagy in gastric cancer. Life Sci, 2020, 244: 117280. doi: 10.1016/j.lfs.2020.117280.
21. Xu Z, Han X, Ou D, et al. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl Microbiol Biotechnol, 2020, 104(2): 575-587.
22. Deng J, Bai X, Feng X, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer, 2019, 19(1): 618. doi: 10.1186/s12885-019-5824-9.
23. 沈二栋, 翁洁, 文芳, 等. 衣霉素诱导的内质网应激对人食管癌细胞自噬和凋亡的影响及其与奥沙利铂化疗耐药的关系. 肿瘤药学, 2019, 9(1): 26-34.
24. 王昌高, 昝慧, 张万里, 等. 胡桃醌对胃癌细胞耐药性及细胞中ANXA2、ERCC1表达和AKT/mTOR信号通路的影响. 胃肠病学和肝病学杂志, 2020, 29(2): 136-141.
25. Wu Q, Ma J, Wei J, et al. FOXD1-AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway. Mol Oncol, 2021, 15(1): 299-316.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Long non-coding RNA MACC1-AS1 mediates cisplatin resistance in gastric cancer through AKT/mTOR pathway

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