Hsa_circ_0050900 affects ferroptosis in intrahepatic cholangiocarcinoma cells by targeting hsa‑miR-605‑3p to regulate SLC3A2

Shi,Xiangtian; Yang,Jiarui; Wang,Meng; Xia,Long; Zhang,Lei; Qiao,Shan

doi:10.3892/ol.2023.14135

Hsa_circ_0050900 affects ferroptosis in intrahepatic cholangiocarcinoma cells by targeting hsa‑miR-605‑3p to regulate SLC3A2

Authors:
- Xiangtian Shi
- Jiarui Yang
- Meng Wang
- Long Xia
- Lei Zhang
- Shan Qiao
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, Bayannur Hospital, Bayannur, Inner Mongolia Autonomous Region 015000, P.R. China, Department of Hepatobiliary, Pancreatic and Splenic Surgery, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong 523058, P.R. China, Department of Hepatobiliary‑Pancreatic‑Splenic Surgery, Inner Mongolia Autonomous Region People's Hospital, Hohhot, Inner Mongolia Autonomous Region 010017, P.R. China, Department of Pancreatic Hepato‑Biliary‑Surgery, The Sixth Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510655, P.R. China
Published online on: November 6, 2023 https://doi.org/10.3892/ol.2023.14135
Article Number: 2
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly lethal hepatobiliary tumor with high aggressiveness. The role of circular RNA (circRNA) in ICC remains to be explored. The present study aimed to investigate whether hsa_circ_0050900 affected ferroptosis in ICC cells by regulating hsa‑microRNA (miR)‑605‑3p/solute carrier family 3 member 2 (SLC3A2). Human ICC cells were cultured and hsa_circ_0050900 expression was evaluated by reverse transcription‑quantitative PCR. hsa_circ_0050900 was knocked down and ferroptosis inhibitor ferrostatin‑1 was added to HuCCT‑1 cells. Following knockdown or overexpression of hsa‑miR‑605‑3p, Fe²⁺, reactive oxygen species (ROS), glutathione peroxidase 4 and SLC3A2 levels were assessed using iron and ROS assay kit or RT‑qPCR and western blotting, respectively. Cell function experiments were performed to examine proliferation and migration abilities. Dual‑luciferase reporter gene and argonaute2‑RNA immunoprecipitation assay verified the relationship among hsa_circ_0050900, hsa‑miR‑605‑3p, and SLC3A2. hsa_circ_0050900 was derived from actinin alpha 4 gene and was elevated in ICC cells. Among HuCCT‑1, QBC‑939, HCCC‑9810, and RBE cell lines, the highest expression was in HuCCT‑1 cells. Inhibition of hsa_circ_0050900 inhibited proliferation and migration by facilitating ICC cell ferroptosis. hsa‑miR‑605‑3p expression was elevated after knocking down hsa_circ_0050900 and hsa‑miR‑605‑3p was negatively regulated by hsa_circ_0050900. In addition, hsa‑miR‑605‑3p targeted SLC3A2. Overexpression of hsa‑miR‑605‑3p regulated SLC3A2 to promote ICC cell ferroptosis and inhibit proliferation and migration. Taken together, knockdown of hsa_circ_0050900 inhibited SLC3A2 expression via sponging hsa‑miR‑605‑3p to promote ICC cell ferroptosis, and finally suppressed proliferation and migration. The present study suggested that hsa_circ_0050900 was a potential therapeutic target for ICC.

View Figures

View References

1	Kelley RK, Bridgewater J, Gores GJ and Zhu AX: Systemic therapies for intrahepatic cholangiocarcinoma. J Hepatol. 72:353–363. 2020. View Article : Google Scholar : PubMed/NCBI
2	Rahnemai-Azar AA, Weisbrod A, Dillhoff M, Schmidt C and Pawlik TM: Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis. Surg Oncol. 26:125–137. 2017. View Article : Google Scholar : PubMed/NCBI
3	Moris D, Palta M, Kim C, Allen PJ, Morse MA and Lidsky ME: Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 73:198–222. 2023. View Article : Google Scholar : PubMed/NCBI
4	Aoki S, Inoue K, Klein S, Halvorsen S, Chen J, Matsui A, Nikmaneshi MR, Kitahara S, Hato T, Chen X, et al: Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma. Gut. 71:185–193. 2022. View Article : Google Scholar : PubMed/NCBI
5	Hewitt DB, Brown ZJ and Pawlik TM: Surgical management of intrahepatic cholangiocarcinoma. Expert Rev Anticancer Ther. 22:27–38. 2022. View Article : Google Scholar : PubMed/NCBI
6	Chen Z, Jiang J, Fu N and Chen L: Targetting ferroptosis for blood cell-related diseases. J Drug Target. 30:244–258. 2022. View Article : Google Scholar : PubMed/NCBI
7	Lei G, Zhuang L and Gan B: Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 22:381–396. 2022. View Article : Google Scholar : PubMed/NCBI
8	Chen J, Li X, Ge C, Min J and Wang F: The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 29:467–480. 2022. View Article : Google Scholar : PubMed/NCBI
9	Li D, Wang Y, Dong C, Chen T, Dong A, Ren J, Li W, Shu G, Yang J, Shen W, et al: CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene. 42:83–98. 2023. View Article : Google Scholar : PubMed/NCBI
10	Zhou P, Chen X, Shi K, Qu H and Xia J: The characteristics, tumorigenicities and therapeutics of cancer stem cells based on circRNAs. Pathol Res Pract. 233:1538222022. View Article : Google Scholar : PubMed/NCBI
11	Li H, Lan T, Liu H, Liu C, Dai J, Xu L, Cai Y, Hou G, Xie K, Liao M, et al: IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology. 75:1402–1419. 2021. View Article : Google Scholar : PubMed/NCBI
12	Lu Q and Fang T: Circular RNA SMARCA5 correlates with favorable clinical tumor features and prognosis, and increases chemotherapy sensitivity in intrahepatic cholangiocarcinoma. J Clin Lab Anal. 34:e231382020. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Xing L, Yang R, Chen H, Wang M, Jiang R, Zhang L and Chen J: The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC. Mol Cancer. 20:912021. View Article : Google Scholar : PubMed/NCBI
14	Chen Q, Wang H, Li Z, Li F, Liang L, Zou Y, Shen H, Li J, Xia Y, Cheng Z, et al: Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription. J Hepatol. 76:135–147. 2022. View Article : Google Scholar : PubMed/NCBI
15	Wang Q, Hao X, Xu G and Lv T: Downregulated KIF3B induced by miR-605-3p inhibits the progression of colon cancer via inactivating Wnt/β-Catenin. J Oncol. 2021:50469812021.PubMed/NCBI
16	Zeng Z, Zhou W, Duan L, Zhang J, Lu X, Jin L and Yu Y: Circular RNA circ-VANGL1 as a competing endogenous RNA contributes to bladder cancer progression by regulating miR-605-3p/VANGL1 pathway. J Cell Physiol. 234:3887–3896. 2019. View Article : Google Scholar : PubMed/NCBI
17	Liu N, Hu G, Wang H, Wang Y and Guo Z: LncRNA BLACAT1 regulates VASP expression via binding to miR-605-3p and promotes giloma development. J Cell Physiol. 234:22144–22152. 2019. View Article : Google Scholar : PubMed/NCBI
18	Hu YL, Feng Y, Chen YY, Liu JZ, Su Y, Li P, Huang H, Mao QS and Xue WJ: SNHG16/miR-605-3p/TRAF6/NF-κB feedback loop regulates hepatocellular carcinoma metastasis. J Cell Mol Med. 24:7637–7651. 2020. View Article : Google Scholar : PubMed/NCBI
19	Fei F, Li X, Xu L, Li D, Zhang Z, Guo X, Yang H, Chen Z and Xing J: CD147-CD98hc complex contributes to poor prognosis of non-small cell lung cancer patients through promoting cell proliferation via the PI3K/Akt signaling pathway. Ann Surg Oncol. 21:4359–4368. 2014. View Article : Google Scholar : PubMed/NCBI
20	Liu C, Li X, Li C, Zhang Z, Gao X, Jia Z, Chen H, Jia Q, Zhao X, Liu J, et al: SLC3A2 is a novel endoplasmic reticulum stress-related signaling protein that regulates the unfolded protein response and apoptosis. PLoS One. 13:e02089932018. View Article : Google Scholar : PubMed/NCBI
21	Palacín M and Kanai Y: The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch. 447:490–494. 2004. View Article : Google Scholar : PubMed/NCBI
22	He J, Liu D, Liu M, Tang R and Zhang D: Characterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumors. Front Mol Biosci. 9:9614102022. View Article : Google Scholar : PubMed/NCBI
23	Koppula P, Zhuang L and Gan B: Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 12:599–620. 2021. View Article : Google Scholar : PubMed/NCBI
24	Digomann D, Linge A and Dubrovska A: SLC3A2/CD98hc, autophagy and tumor radioresistance: A link confirmed. Autophagy. 15:1850–1851. 2019. View Article : Google Scholar : PubMed/NCBI
25	Ma L, Zhang X, Yu K, Xu X, Chen T, Shi Y, Wang Y, Qiu S, Guo S, Cui J, et al: Targeting SLC3A2 subunit of system X_C⁻ is essential for m⁶A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma. Free Radic Biol Med. 168:25–43. 2021. View Article : Google Scholar : PubMed/NCBI
26	Wu F, Xiong G, Chen Z, Lei C, Liu Q and Bai Y: SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway. Hereditas. 159:62022. View Article : Google Scholar : PubMed/NCBI
27	Liu H, Deng Z, Yu B, Liu H, Yang Z, Zeng A and Fu M: Identification of SLC3A2 as a potential therapeutic target of osteoarthritis involved in ferroptosis by integrating bioinformatics, clinical factors and experiments. Cells. 11:34302022. View Article : Google Scholar : PubMed/NCBI
28	Hu Z, Yin Y, Jiang J, Yan C, Wang Y, Wang D and Li L: Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression. J Gastrointest Oncol. 13:754–767. 2022. View Article : Google Scholar : PubMed/NCBI
29	Qin X, Zhang J, Wang B, Xu G, Yang X, Zou Z and Yu C: Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells. Autophagy. 17:4266–4285. 2021. View Article : Google Scholar : PubMed/NCBI
30	Shang A, Gu C, Wang W, Wang X, Sun J, Zeng B, Chen C, Chang W, Ping Y, Ji P, et al: Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis. Mol Cancer. 19:1172020. View Article : Google Scholar : PubMed/NCBI
31	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
32	Krenzien F, Nevermann N, Krombholz A, Benzing C, Haber P, Fehrenbach U, Lurje G, Pelzer U, Pratschke J, Schmelzle M and Schöning W: Treatment of intrahepatic cholangiocarcinoma-a multidisciplinary approach. Cancers (Basel). 14:3622022. View Article : Google Scholar : PubMed/NCBI
33	Yang J, Qi M, Fei X, Wang X and Wang K: Hsa_circRNA_0088036 acts as a ceRNA to promote bladder cancer progression by sponging miR-140-3p. Cell Death Dis. 13:3222022. View Article : Google Scholar : PubMed/NCBI
34	Du J, Lan T, Liao H, Feng X, Chen X, Liao W, Hou G, Xu L, Feng Q, Xie K, et al: CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma. Mol Cancer. 21:182022. View Article : Google Scholar : PubMed/NCBI
35	Jiang XM, Li ZL, Li JL, Xu Y, Leng KM, Cui YF and Sun DJ: A novel prognostic biomarker for cholangiocarcinoma: circRNA Cdr1as. Eur Rev Med Pharmacol Sci. 22:365–371. 2018.PubMed/NCBI
36	Zhou D, Gao B, Yang Q, Kong Y and Wang W: Integrative analysis of ceRNA network reveals functional lncRNAs in intrahepatic cholangiocarcinoma. Biomed Res Int. 2019:26012712019. View Article : Google Scholar : PubMed/NCBI
37	Kang Z, Guo L, Zhu Z and Qu R: Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network. Cancer Cell Int. 20:3152020. View Article : Google Scholar : PubMed/NCBI
38	Xu YP, Dong ZN, Wang SW, Zheng YM, Zhang C, Zhou YQ, Zhao YJ, Zhao Y, Wang F, Peng R, et al: circHMGCS1-016 reshapes immune environment by sponging miR-1236-3p to regulate CD73 and GAL-8 expression in intrahepatic cholangiocarcinoma. J Exp Clin Cancer Res. 40:2902021. View Article : Google Scholar : PubMed/NCBI
39	Tang J, Wang R, Tang R, Gu P, Han J and Huang W: CircRTN4IP1 regulates the malignant progression of intrahepatic cholangiocarcinoma by sponging miR-541-5p to induce HIF1A production. Pathol Res Pract. 230:1537322022. View Article : Google Scholar : PubMed/NCBI
40	Cano-Crespo S, Chillarón J, Junza A, Fernández-Miranda G, García J, Polte C, R de la Ballina L, Ignatova Z, Yanes Ó, Zorzano A, et al: CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression. Sci Rep. 9:140652019. View Article : Google Scholar : PubMed/NCBI
41	Furuya M, Horiguchi J, Nakajima H, Kanai Y and Oyama T: Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci. 103:382–389. 2012. View Article : Google Scholar : PubMed/NCBI
42	Zhu B, Cheng D, Hou L, Zhou S, Ying T and Yang Q: SLC3A2 is upregulated in human osteosarcoma and promotes tumor growth through the PI3K/Akt signaling pathway. Oncol Rep. 37:2575–2582. 2017. View Article : Google Scholar : PubMed/NCBI
43	Li W, Dong X, He C, Tan G, Li Z, Zhai B, Feng J, Jiang X, Liu C, Jiang H and Sun X: LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. J Exp Clin Cancer Res. 38:1832019. View Article : Google Scholar : PubMed/NCBI
44	Janpipatkul K, Suksen K, Borwornpinyo S, Jearawiriyapaisarn N, Hongeng S, Piyachaturawat P and Chairoungdua A: Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration. Cell Signal. 26:1668–1679. 2014. View Article : Google Scholar : PubMed/NCBI