Current Medicinal Chemistry

Author(s): Xinyan Qiu and Jinlan Chen*

DOI: 10.2174/0929867330666230123144602

LSINCT5: A Novel lncRNA in Cancers

Page: [4409 - 4420] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Long chain non-coding RNAs (lncRNA) are a kind of transcript that is around 200 nucleotides long and can engage in life activities via epigenetic, transcriptional, and post-transcriptional regulation. One of the key members of lncRNAs, long stress-induced noncoding transcripts 5 (LSINCT5), is localized at Chr 5p and has been reported to be abnormally expressed in a range of cancers. We present a comprehensive review of LSINCT5's aberrant expression and regulatory mechanisms in malignant tumors.

Methods: The included studies were retrieved and summarized through the PubMed database using the keywords “LSINCT5” and “Cancer” in detail.

Results: LSINCT5 behaves as an oncogene and abundantly expresses in malignant tumorigenesis and progression. By sponging microRNAs (miRNA), interacting with proteins, participating in cellular transduction, and being regulated by transcription factors, LSINCT5 can stimulate malignant behavior in a variety of tumor cells, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Furthermore, dysregulated LSINCT5 is usually associated with a poor prognosis.

Conclusion: LSINCT5 has the potential to become a tumor diagnostic and prognostic marker, generating new access to clinical applications.

[1]
Yang, Z.; Jiang, S.; Shang, J.; Jiang, Y.; Dai, Y.; Xu, B.; Yu, Y.; Liang, Z.; Yang, Y. LncRNA: Shedding light on mechanisms and opportunities in fibrosis and aging. Ageing Res. Rev., 2019, 52, 17-31.
[http://dx.doi.org/10.1016/j.arr.2019.04.001] [PMID: 30954650]
[2]
Yan, Y.; Xu, Z.; Li, Z.; Sun, L.; Gong, Z. An insight into the increasing role of LncRNAs in the pathogenesis of gliomas. Front. Mol. Neurosci., 2017, 10, 53.
[http://dx.doi.org/10.3389/fnmol.2017.00053] [PMID: 28293170]
[3]
Dykes, I.M.; Emanueli, C. Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genom. Proteom. Bioinform., 2017, 15(3), 177-186.
[http://dx.doi.org/10.1016/j.gpb.2016.12.005] [PMID: 28529100]
[4]
Teng, P.C.; Liang, Y.; Yarmishyn, A.A.; Hsiao, Y.J.; Lin, T.Y.; Lin, T.W.; Teng, Y.C.; Yang, Y.P.; Wang, M.L.; Chien, C.S.; Luo, Y.H.; Chen, Y.M.; Hsu, P.K.; Chiou, S.H.; Chien, Y. RNA modifications and epigenetics in modulation of lung cancer and pulmonary diseases. Int. J. Mol. Sci., 2021, 22(19), 10592.
[http://dx.doi.org/10.3390/ijms221910592] [PMID: 34638933]
[5]
Liu, W.; Ma, R.; Yuan, Y. Post-transcriptional regulation of genes related to biological behaviors of gastric cancer by long noncoding RNAs and MicroRNAs. J. Cancer, 2017, 8(19), 4141-4154.
[http://dx.doi.org/10.7150/jca.22076] [PMID: 29187891]
[6]
Goyal, B.; Yadav, S.R.M.; Awasthee, N.; Gupta, S.; Kunnumakkara, A.B.; Gupta, S.C. Diagnostic, prognostic, and therapeutic significance of long non-coding RNA MALAT1 in cancer. Biochim. Biophys. Acta Rev. Cancer, 2021, 1875(2), 188502.
[http://dx.doi.org/10.1016/j.bbcan.2021.188502] [PMID: 33428963]
[7]
Joshi, M.; Rajender, S. Long non-coding RNAs (lncRNAs) in spermatogenesis and male infertility. Reprod. Biol. Endocrinol., 2020, 18(1), 103.
[http://dx.doi.org/10.1186/s12958-020-00660-6] [PMID: 33126901]
[8]
Aich, M.; Chakraborty, D. Role of lncRNAs in stem cell maintenance and differentiation. Curr. Top. Dev. Biol., 2020, 138, 73-112.
[http://dx.doi.org/10.1016/bs.ctdb.2019.11.003] [PMID: 32220299]
[9]
Lin, Y.H. Crosstalk of lncRNA and cellular metabolism and their regulatory mechanism in cancer. Int. J. Mol. Sci., 2020, 21(8), 2947.
[http://dx.doi.org/10.3390/ijms21082947] [PMID: 32331347]
[10]
Silva, J.M.; Boczek, N.J.; Berres, M.W.; Ma, X.; Smith, D.I. LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol., 2011, 8(3), 496-505.
[http://dx.doi.org/10.4161/rna.8.3.14800] [PMID: 21532345]
[11]
Tong, X.; Chen, J.; Liu, W.; Liang, H.; Zhu, H. LncRNA LSINCT5/miR-222 regulates myocardial ischemia-reperfusion injury through PI3K/AKT pathway. J. Thromb. Thrombolysis, 2021, 52(3), 720-729.
[http://dx.doi.org/10.1007/s11239-021-02506-3] [PMID: 34184201]
[12]
Wang, X.; Feng, X.; Wang, H. LncRNA LSINCT5 drives proliferation and migration of oral squamous cell carcinoma through the miRNA-185-5p/ZNF703 axis. J. BUON, 2021, 26(1), 124-131.
[PMID: 33721442]
[13]
Jing, L.; Lin, J.; Zhao, Y.; Liu, G.J.; Liu, Y.B.; Feng, L.; Yang, H.Y.; Cui, W.X.; Zhang, X.H. Long noncoding RNA LSINCT5 is upregulated and promotes the progression of esophageal squamous cell carcinoma. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(12), 5195-5205.
[PMID: 31298370]
[14]
Qi, P.; Lin, W.; Zhang, M.; Huang, D.; Ni, S.; Zhu, X.; Bai, Q.; Sheng, W.; Du, X.; Zhou, X. E2F1 induces LSINCT5 transcriptional activity and promotes gastric cancer progression by affecting the epithelial-mesenchymal transition. Cancer Manag. Res., 2018, 10, 2563-2571.
[http://dx.doi.org/10.2147/CMAR.S171652] [PMID: 30127643]
[15]
Li, O.; Li, Z.; Tang, Q.; Li, Y.; Yuan, S.; Shen, Y.; Zhang, Z.; Li, N.; Chu, K.; Lei, G. Long Stress Induced Non-Coding Transcripts 5 (LSINCT5) promotes hepatocellular carcinoma progression through interaction with high-mobility group AT-hook 2 and MiR-4516. Med. Sci. Monit., 2018, 24, 8510-8523.
[http://dx.doi.org/10.12659/MSM.911179] [PMID: 30472720]
[16]
Tian, Y.; Zhang, N.; Chen, S.; Ma, Y.; Liu, Y. The long non-coding RNA LSINCT5 promotes malignancy in non-small cell lung cancer by stabilizing HMGA2. Cell Cycle, 2018, 17(10), 1188-1198.
[http://dx.doi.org/10.1080/15384101.2018.1467675] [PMID: 29883241]
[17]
Dai, Y.; Wu, L.; Zhang, Z.; Ou, Y.; Huang, J. Effects of knockout of long-chain non-coding RNA LSINCT5 on proliferation, apoptosis, epithelial-mesenchymal transition, and p38MAPK pathway of pancreatic cancer PANC-1 cells. Transl. Cancer Res., 2020, 9(3), 1418-1426.
[http://dx.doi.org/10.21037/tcr.2020.01.50] [PMID: 35117489]
[18]
Zhang, G.; Song, W. Long non-coding RNA LSINCT5 inactivates Wnt/β-catenin pathway to regulate MCF-7 cell proliferation and motility through targeting the miR-30a. Ann. Transl. Med., 2020, 8(24), 1635.
[http://dx.doi.org/10.21037/atm-20-7253] [PMID: 33490147]
[19]
Long, X.; Li, L.; Zhou, Q.; Wang, H.; Zou, D.; Wang, D.; Lou, M.; Nian, W. Long non-coding RNA LSINCT5 promotes ovarian cancer cell proliferation, migration and invasion by disrupting the CXCL12/CXCR4 signalling axis. Oncol. Lett., 2018, 15(5), 7200-7206.
[http://dx.doi.org/10.3892/ol.2018.8241] [PMID: 29755595]
[20]
Jiang, H.; Li, Y.; Li, J.; Zhang, X.; Niu, G.; Chen, S.; Yao, S. Long noncoding RNA LSINCT5 promotes endometrial carcinoma cell proliferation, cycle, and invasion by promoting the Wnt/β-catenin signaling pathway via HMGA2. Ther. Adv. Med. Oncol., 2019, 11, 1758835919874649.
[http://dx.doi.org/10.1177/1758835919874649] [PMID: 31632465]
[21]
Zhu, X.; Li, Y.; Zhao, S.; Zhao, S. LSINCT5 activates Wnt/β-catenin signaling by interacting with NCYM to promote bladder cancer progression. Biochem. Biophys. Res. Commun., 2018, 502(3), 299-306.
[http://dx.doi.org/10.1016/j.bbrc.2018.05.076] [PMID: 29772237]
[22]
Jin, Z.; Piao, L.; Sun, G.; Lv, C.; Jing, Y.; Jin, R. Dual functional nanoparticles efficiently across the blood–brain barrier to combat glioblastoma via simultaneously inhibit the PI3K pathway and NKG2A axis. J. Drug Target., 2021, 29(3), 323-335.
[http://dx.doi.org/10.1080/1061186X.2020.1841214] [PMID: 33108906]
[23]
He, W.; Lu, M.; Xiao, D. LSINCT5 predicts unfavorable prognosis and exerts oncogenic function in osteosarcoma. Biosci. Rep., 2019, 39(5), BSR20190612.
[http://dx.doi.org/10.1042/BSR20190612] [PMID: 30967495]
[24]
Kong, D.; Li, C.; Yang, Q.; wei, B.; Wang, L.; Peng, C. Long noncoding RNA LSINCT5 acts as an oncogene via increasing EZH2-induced inhibition of APC expression in osteosarcoma. Biochem. Biophys. Res. Commun., 2018, 507(1-4), 193-197.
[http://dx.doi.org/10.1016/j.bbrc.2018.11.005] [PMID: 30420287]
[25]
Hübbers, C.U.; Akgül, B. HPV and cancer of the oral cavity. Virulence, 2015, 6(3), 244-248.
[http://dx.doi.org/10.1080/21505594.2014.999570] [PMID: 25654476]
[26]
D’Souza, W.; Kumar, A. microRNAs in oral cancer: Moving from bench to bed as next generation medicine. Oral Oncol., 2020, 111, 104916.
[http://dx.doi.org/10.1016/j.oraloncology.2020.104916] [PMID: 32711289]
[27]
Lei, C.S.; Kung, H.J.; Shih, J.W. Long non-coding RNAs as functional codes for oral cancer: Translational potential, progress and promises. Int. J. Mol. Sci., 2021, 22(9), 4903.
[http://dx.doi.org/10.3390/ijms22094903] [PMID: 34063159]
[28]
Wang, Y.; Wu, Z.; Li, Y.; Zheng, Z.; Yan, J.; Tian, S.; Han, L. Long non-coding RNA H19 promotes proliferation, migration and invasion and inhibits apoptosis of breast cancer cells by targeting miR-491-5p/ZNF703 axis. Cancer Manag. Res., 2020, 12, 9247-9258.
[http://dx.doi.org/10.2147/CMAR.S246009] [PMID: 33061615]
[29]
Ohashi, S.; Miyamoto, S.; Kikuchi, O.; Goto, T.; Amanuma, Y.; Muto, M. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology, 2015, 149(7), 1700-1715.
[http://dx.doi.org/10.1053/j.gastro.2015.08.054] [PMID: 26376349]
[30]
Tang, Y.; Yang, P.; Zhu, Y.; Su, Y. LncRNA TUG1 contributes to ESCC progression via regulating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro. Thorac. Cancer, 2020, 11(1), 82-94.
[http://dx.doi.org/10.1111/1759-7714.13236] [PMID: 31742924]
[31]
Zhang, X.; Zhang, P. Gastric cancer: Somatic genetics as a guide to therapy. J. Med. Genet., 2017, 54(5), 305-312.
[http://dx.doi.org/10.1136/jmedgenet-2016-104171] [PMID: 27609016]
[32]
Wei, L.; Sun, J.; Zhang, N.; Zheng, Y.; Wang, X.; Lv, L.; Liu, J.; Xu, Y.; Shen, Y.; Yang, M. Noncoding RNAs in gastric cancer: Implications for drug resistance. Mol. Cancer, 2020, 19(1), 62.
[http://dx.doi.org/10.1186/s12943-020-01185-7] [PMID: 32192494]
[33]
Chun, J.N.; Cho, M.; Park, S.; So, I.; Jeon, J.H. The conflicting role of E2F1 in prostate cancer: A matter of cell context or interpretational flexibility? Biochim. Biophys. Acta Rev. Cancer, 2020, 1873(1), 188336.
[http://dx.doi.org/10.1016/j.bbcan.2019.188336] [PMID: 31870703]
[34]
Huang, Z.; Zhou, J.K.; Peng, Y.; He, W.; Huang, C. The role of long noncoding RNAs in hepatocellular carcinoma. Mol. Cancer, 2020, 19(1), 77.
[http://dx.doi.org/10.1186/s12943-020-01188-4] [PMID: 32295598]
[35]
Degasperi, E.; Colombo, M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol. Hepatol., 2016, 1(2), 156-164.
[http://dx.doi.org/10.1016/S2468-1253(16)30018-8] [PMID: 28404072]
[36]
Nagano, T.; Tachihara, M.; Nishimura, Y. Molecular mechanisms and targeted therapies including immunotherapy for non-small cell lung cancer. Curr. Cancer Drug Targets, 2019, 19(8), 595-630.
[http://dx.doi.org/10.2174/1568009619666181210114559] [PMID: 30526458]
[37]
Boo, L.M.; Lin, H.H.; Chung, V.; Zhou, B.; Louie, S.G.; O’Reilly, M.A.; Yen, Y.; Ann, D.K. High mobility group A2 potentiates genotoxic stress in part through the modulation of basal and DNA damage-dependent phosphatidylinositol 3-kinase-related protein kinase activation. Cancer Res., 2005, 65(15), 6622-6630.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-0086] [PMID: 16061642]
[38]
Huang, X.; Zhi, X.; Gao, Y.; Ta, N.; Jiang, H.; Zheng, J. LncRNAs in pancreatic cancer. Oncotarget, 2016, 7(35), 57379-57390.
[http://dx.doi.org/10.18632/oncotarget.10545] [PMID: 27429196]
[39]
Klein, A.P. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat. Rev. Gastroenterol. Hepatol., 2021, 18(7), 493-502.
[http://dx.doi.org/10.1038/s41575-021-00457-x] [PMID: 34002083]
[40]
Alam, M.S.; Gaida, M.M.; Bergmann, F.; Lasitschka, F.; Giese, T.; Giese, N.A.; Hackert, T.; Hinz, U.; Hussain, S.P.; Kozlov, S.V.; Ashwell, J.D. Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. Nat. Med., 2015, 21(11), 1337-1343.
[http://dx.doi.org/10.1038/nm.3957] [PMID: 26479921]
[41]
Liang, Y.; Zhang, H.; Song, X.; Yang, Q. Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets. Semin. Cancer Biol., 2020, 60, 14-27.
[http://dx.doi.org/10.1016/j.semcancer.2019.08.012] [PMID: 31421262]
[42]
Wörmann, B. Breast cancer: basics, screening, diagnostics and treatment. Med. Monatsschr. Pharm., 2017, 40(2), 55-64.
[PMID: 29952495]
[43]
Torkashvand, S.; Basi, A.; Ajdarkosh, H.; Rakhshani, N.; Nafisi, N.; Mowla, S.J.; Moghadas, A.; Mohammadipour, M.; Karbalaie Niya, M.H. Long non-coding RNAs expression in breast cancer: CBR3-AS1 LncRNA as a sensitive biomarker. Asian Pac. J. Cancer Prev., 2021, 22(9), 2897-2902.
[http://dx.doi.org/10.31557/APJCP.2021.22.9.2897] [PMID: 34582659]
[44]
Liu, J.; Xiao, Q.; Xiao, J.; Niu, C.; Li, Y.; Zhang, X.; Zhou, Z.; Shu, G.; Yin, G. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct. Target. Ther., 2022, 7(1), 3.
[http://dx.doi.org/10.1038/s41392-021-00762-6] [PMID: 34980884]
[45]
Bilbao, M.; Aikins, J.K.; Ostrovsky, O. Is routine omentectomy of grossly normal omentum helpful in surgery for ovarian cancer? A look at the tumor microenvironment and its clinical implications. Gynecol. Oncol., 2021, 161(1), 78-82.
[http://dx.doi.org/10.1016/j.ygyno.2020.12.033] [PMID: 33436287]
[46]
Wang, X.; Wang, Y.; Sun, F.; Xu, Y.; Zhang, Z.; Yang, C.; Zhang, L.; Lou, G. Novel LncRNA ZFHX4-AS1 as a potential prognostic biomarker that affects the immune microenvironment in ovarian cancer. Front. Oncol., 2022, 12, 945518.
[http://dx.doi.org/10.3389/fonc.2022.945518] [PMID: 35903691]
[47]
Izumi, D.; Ishimoto, T.; Miyake, K.; Sugihara, H.; Eto, K.; Sawayama, H.; Yasuda, T.; Kiyozumi, Y.; Kaida, T.; Kurashige, J.; Imamura, Y.; Hiyoshi, Y.; Iwatsuki, M.; Iwagami, S.; Baba, Y.; Sakamoto, Y.; Miyamoto, Y.; Yoshida, N.; Watanabe, M.; Takamori, H.; Araki, N.; Tan, P.; Baba, H. CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer. Int. J. Cancer, 2016, 138(5), 1207-1219.
[http://dx.doi.org/10.1002/ijc.29864] [PMID: 26414794]
[48]
Liu, G.; Wang, Y.; Zhang, X.; Yuan, B.; Han, C.; Xue, F. Endometrial carcinoma in a 15-year-old obese patient with persistent uterine bleeding. Gynecol. Endocrinol., 2014, 30(4), 277-279.
[http://dx.doi.org/10.3109/09513590.2013.875156] [PMID: 24456540]
[49]
Kong, Y.; Ren, Z. Overexpression of LncRNA FER1L4 in endometrial carcinoma is associated with favorable survival outcome. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(23), 8113-8118.
[PMID: 30556848]
[50]
Fan, J.T.; Zhou, Z.Y.; Luo, Y.L.; Luo, Q.; Chen, S.B.; Zhao, J.C.; Chen, Q.R. Exosomal lncRNA NEAT1 from cancer-associated fibroblasts facilitates endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 signaling pathway. Neoplasia, 2021, 23(7), 692-703.
[http://dx.doi.org/10.1016/j.neo.2021.05.004] [PMID: 34153644]
[51]
Du, Y.; Wang, L.; Chen, S.; Liu, Y.; Zhao, Y. lncRNA DLEU1 contributes to tumorigenesis and development of endometrial carcinoma by targeting mTOR. Mol. Carcinog., 2018, 57(9), 1191-1200.
[http://dx.doi.org/10.1002/mc.22835] [PMID: 29745433]
[52]
Seidl, C. Targets for therapy of bladder cancer. Semin. Nucl. Med., 2020, 50(2), 162-170.
[http://dx.doi.org/10.1053/j.semnuclmed.2020.02.006] [PMID: 32172801]
[53]
Zhang, Q.; Su, M.; Lu, G.; Wang, J. The complexity of bladder cancer: long noncoding RNAs are on the stage. Mol. Cancer, 2013, 12(1), 101.
[http://dx.doi.org/10.1186/1476-4598-12-101] [PMID: 24006935]
[54]
Suenaga, Y.; Islam, S.M.R.; Alagu, J.; Kaneko, Y.; Kato, M.; Tanaka, Y.; Kawana, H.; Hossain, S.; Matsumoto, D.; Yamamoto, M.; Shoji, W.; Itami, M.; Shibata, T.; Nakamura, Y.; Ohira, M.; Haraguchi, S.; Takatori, A.; Nakagawara, A. NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas. PLoS Genet., 2014, 10(1), e1003996.
[http://dx.doi.org/10.1371/journal.pgen.1003996] [PMID: 24391509]
[55]
Albrecht, L.V.; Tejeda-Muñoz, N.; Bui, M.H.; Cicchetto, A.C.; Di Biagio, D.; Colozza, G.; Schmid, E.; Piccolo, S.; Christofk, H.R.; De Robertis, E.M. GSK3 inhibits macropinocytosis and lysosomal activity through the Wnt destruction complex machinery. Cell Rep., 2020, 32(4), 107973.
[http://dx.doi.org/10.1016/j.celrep.2020.107973] [PMID: 32726636]
[56]
Ostrom, Q.T.; Gittleman, H.; Stetson, L.; Virk, S.M.; Barnholtz-Sloan, J.S. Epidemiology of Gliomas. Cancer Treat. Res., 2015, 163, 1-14.
[http://dx.doi.org/10.1007/978-3-319-12048-5_1] [PMID: 25468222]
[57]
Wu, D.; Sun, J.; Wang, H.; Ma, C. LncRNA SOCS2-AS1 promotes the progression of glioma via regulating ITGB1 expression. Neurosci. Lett., 2021, 765, 136248.
[http://dx.doi.org/10.1016/j.neulet.2021.136248] [PMID: 34536509]
[58]
Bai, H.; Wu, S. miR-451: A novel biomarker and potential therapeutic target for cancer. OncoTargets Ther., 2019, 12, 11069-11082.
[http://dx.doi.org/10.2147/OTT.S230963] [PMID: 31908476]
[59]
Cardama, G.A.; Gonzalez, N.; Ciarlantini, M.; Gandolfi Donadío, L.; Comin, M.J.; Alonso, D.F.; Menna, P.L.; Gomez, D.E. Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells. OncoTargets Ther., 2014, 7, 2021-2033.
[PMID: 25378937]
[60]
Coventon, J. A review of the mechanism of action and clinical applications of sorafenib in advanced osteosarcoma. J. Bone Oncol., 2017, 8, 4-7.
[http://dx.doi.org/10.1016/j.jbo.2017.07.001] [PMID: 28828294]
[61]
Ghafouri-Fard, S.; Shirvani-Farsani, Z.; Hussen, B.M.; Taheri, M. The critical roles of lncRNAs in the development of osteosarcoma. Biomed. Pharmacother., 2021, 135, 111217.
[http://dx.doi.org/10.1016/j.biopha.2021.111217] [PMID: 33433358]
[62]
Jiang, R.; Zhang, C.; Liu, G.; Gu, R.; Wu, H. MicroRNA-107 promotes proliferation, migration, and invasion of osteosarcoma cells by targeting Tropomyosin 1. Oncol. Res., 2017, 25(8), 1409-1419.
[http://dx.doi.org/10.3727/096504017X14882829077237] [PMID: 28276320]
[63]
Hao, A.; Wang, Y.; Stovall, D.B.; Wang, Y.; Sui, G. Emerging roles of LncRNAs in the EZH2-regulated oncogenic network. Int. J. Biol. Sci., 2021, 17(13), 3268-3280.
[http://dx.doi.org/10.7150/ijbs.63488] [PMID: 34512145]