MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer
Liurong Liu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Department of General Surgery, Yancheng Third People's Hospital, Yancheng, Jiangsu, China
Search for more papers by this authorHuihui Yao
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorXin Zhou
Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorJunjie Chen
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuoliang Chen
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorXinyu Shi
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuanting Wu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuoqiang Zhou
Department of Gastrointestinal Surgery, Changshu No. 2 Hospital, Suzhou, Jiangsu, China
Search for more papers by this authorCorresponding Author
Songbing He
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Correspondence Songbing He, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
Email: [email protected].
Search for more papers by this authorLiurong Liu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Department of General Surgery, Yancheng Third People's Hospital, Yancheng, Jiangsu, China
Search for more papers by this authorHuihui Yao
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorXin Zhou
Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorJunjie Chen
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuoliang Chen
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorXinyu Shi
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuanting Wu
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Search for more papers by this authorGuoqiang Zhou
Department of Gastrointestinal Surgery, Changshu No. 2 Hospital, Suzhou, Jiangsu, China
Search for more papers by this authorCorresponding Author
Songbing He
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Correspondence Songbing He, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.
Email: [email protected].
Search for more papers by this authorLiurong Liu and Huihui Yao contributed equally to this work.
Abstract
Colorectal cancer (CRC) is the second most common cancer-related deaths throughout the world. Ferroptosis is a recently regulated form of cell death, lately gains attention. MicroRNA-15a-3p (miR-15a-3p) plays a regulatory role in various kinds of cancers. However, the role of miR-15a-3p in cellular ferroptosis is still unclear. Here, we aimed to clarify whether miR-15a-3p could regulate the ferroptosis of CRC. Here we identified miR-15a-3p positively regulates ferroptosis via directly targeting glutathione peroxidase glutathione peroxidase 4 (GPX4) in CRC. Overexpression of miR-15a-3p repressed GPX4 through binding to the 3′-untranslated region of GPX4, resulting in increased reactive oxygen species level, intracellular Fe2+ level, and malondialdehyde accumulation in vitro and in vivo. Correspondingly, suppression of miR-15a-3p reduced the sensitivity of CRC cells to erastin and GPX4. Taken together, these data demonstrate that miR-15a-3p regulates ferroptosis through targeting GPX4 in CRC cells, illustrating the novel role of microRNA in ferroptosis.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
The data used in the current study are available from the corresponding author on reasonable request.
REFERENCES
- 1Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005; 352: 476-487.
- 2Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colorectal Rectal Surg. 2009; 22: 191-197.
- 3Nishina T, Takano Y, Denda T, et al. A phase II clinical study of mFOLFOX6 plus bevacizumab as first-line therapy for Japanese advanced/recurrent colorectal cancer patients. Jpn J Clin Oncol. 2013; 43(11): 1080-1086.
- 4Brulé SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015; 51(11): 1405-1414.
- 5Miller S, Steele S. Novel molecular screening approaches in colorectal cancer. J Surg Oncol. 2012; 05: 459-467.
- 6Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5): 1060-1072.
- 7Guan P, Shi ZH, Li YQ, Wang N. Ferroptosis: a new mechanism of cell death. Prog Biochem Biophys. 2013; 40: 137-140.
- 8Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016; 26(3): 165-176.
- 9Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016; 73(11-12): 2195-2209. doi:10.1007/s00018-016-2194-1
- 10Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016; 23(3): 369-379. doi:10.1038/cdd.2015.158
- 11Bertrand RL. Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events. Med Hypotheses. 2017; 101: 69-74. doi:10.1016/j.mehy.2017.02.017
- 12Xie Y, Zhu S, Song X, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017; 20(7): 1692-1704.
- 13Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015; 59(2): 298-308.
- 14Dächert J, Schoeneberger H, Rohde K, Fulda S. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death. Oncotarget. 2016; 7(39): 63779-63792.
- 15Sato M, Kusumi R, Hamashima S, et al. The ferroptosis inducer erastin irreversibly inhibits system xc- and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells. Sci Rep. 2018; 8(1): 968.
- 16Shintoku R, Takigawa Y, Yamada K, et al. Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci. 2017; 108(11): 2187-2194.
- 17Zhang T, Zheng P, Shen X, et al. Curcuminoid WZ26, a TrxR1 inhibitor, effectively inhibits colon cancer cell growth and enhances cisplatin-induced cell death through the induction of ROS. Free Radic Biol Med. 2019; 141: 93-102.
- 18Park S, Oh J, Kim M, Jin EJ. Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis. Anim Cells Syst (Seoul). 2018; 22(5): 334-340.
- 19Lee YS, Lee DH, Jeong SY, et al. Ferroptosis-inducing agents enhance TRAIL-induced apoptosis through upregulation of death receptor 5. J Cell Biochem. 2019; 120(1): 928-939.
- 20Shen Z, Song J, Yung BC, Zhou Z, Wu A, Chen X. Emerging strategies of cancer therapy based on ferroptosis. Adv Mater. 2018; 30(12):e1704007.
- 21Ambros V. The functions of animal microRNAs. Nature. 2004; 431(7006): 350-355.
- 22Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2): 281-297.
- 23Bai T, Liang R, Zhu R, Wang W, Zhou L, Sun Y. MicroRNA-214-3p enhances Erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol. 2020; 235(7-8): 5637-5648.
- 24Luo M, Wu L, Zhang K, et al. miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ. 2018; 25(8): 1457-1472.
- 25Zhang K, Wu L, Zhang P, et al. miR-9 regulates ferroptosis by targeting glutamic-oxaloacetic transaminase GOT1 in melanoma. Mol Carcinog. 2018; 57(11): 1566-1576.
- 26Cui Y, Yang Y, Ren L, et al. miR-15a-3p suppresses prostate cancer cell proliferation and invasion by targeting SLC39A7 Via downregulating Wnt/β-catenin signaling pathway. Cancer Biother Radiopharm. 2019; 34(7): 472-479.
- 27Wu Y, Huang J, Xu H, Gong Z. Over-expression of miR-15a-3p enhances the radiosensitivity of cervical cancer by targeting tumor protein D52. Biomed Pharmacother. 2018; 105: 1325-1334.
- 28Wang S, Zhang S, He Y, Huang X, Hui Y, Tang Y. HOXA11-AS regulates JAK-STAT pathway by miR-15a-3p/STAT3 axis to promote the growth and metastasis in liver cancer. J Cell Biochem. 2019; 120(9): 15941-15951.
- 29de Groen FL, Timmer LM, Menezes RX, et al. Oncogenic role of miR-15a-3p in 13q amplicon-driven colorectal adenoma-to-carcinoma progression. PLoS One. 2015; 10(7):e0132495.
- 30Fan B, Chen LP, Yuan YH, Xiao HN, Lv XS, Xia ZY. MiR-15a-3p suppresses the growth and metastasis of ovarian cancer cell by targeting Twist1. Eur Rev Med Pharmacol Sci. 2019; 23(5): 1934-1946.
- 31Wang D, Wu W, Huang W, Wang J, Luo L, Tang D. LncRNA LUADT1 sponges miR-15a-3p to upregulate Twist1 in small cell lung cancer. BMC Pulm Med. 2019; 19(1): 246.
- 32Wang T, Hou J, Li Z, et al. miR-15a-3p and miR-16-1-3p negatively regulate Twist1 to repress gastric cancer cell invasion and metastasis. Int J Biol Sci. 2017; 13(1): 122-134.
- 33An P, Gao Z, Sun K, et al. Photothermal-enhanced inactivation of glutathione peroxidase for ferroptosis sensitized by an autophagy promotor. ACS Appl Mater Interfaces. 2019; 11(46): 42988-42997.
- 34Sui X, Zhang R, Liu S, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Front Pharmacol. 2018; 9: 1371.
- 35Wang Y, Chen Q, Shi C, Jiao F, Gong Z. Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress. Mol Med Rep. 2019; 20(5): 4081-4090.
- 36Peng G, Tang Z, Xiang Y, Chen W. Glutathione peroxidase 4 maintains a stemness phenotype, oxidative homeostasis and regulates biological processes in Panc-1 cancer stem-like cells. Oncol Rep. 2019; 41(2): 1264-1274.
- 37Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017; 12: 8-17.
- 38Kim JH. Chemotherapy for colorectal cancer in the elderly. World J Gastroenterol. 2015; 21: 5158-5166.
- 39Zhang X, Sui S, Wang L, et al. Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J Cell Physiol. 2020; 235(4): 3425-3437.