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Role of Nischarin in the pathology of diseases: a special emphasis on breast cancer

Oncogene volume 41, pages 1079–1086 (2022)Cite this article

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Abstract

Nischarin has been demonstrated to have tumor suppressor functions. In this review, we comprehensively discuss up to date information about Nischarin. In addition, this paper aims to report the prognostic value, clinical relevance, and biological significance of the Nischarin gene (NISCH) in breast cancer (BCa) patients using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) datasets. We evaluated NISCH gene expression and its correlation to patient survival, baseline expression, and expression variation based on age groups, tumor stage, tumor size, tumor grade, and lymph node status in different subtypes of BCa. Since NISCH has been extensively reported to inhibit EMT and cancer cell migration, we also checked for the correlation between NISCH and EMT genes in addition to the correlation between NISCH and cell migration genes. Our results indicate that NISCH is a tumor suppressor that plays a critical role in BCa initiation, progression, and tumor development. We find that there is a higher level of NISCH expression in normal breast tissues compared to breast cancer tissues. Also, aggressive subtypes of breast cancers, such as the triple negative/basal category, have decreased levels of NISCH as the disease progresses. Finally, we report that NISCH is inversely correlated with many EMT and cancer cell migration genes in BCa. Interestingly, we identified a significant negative correlation between NISCH expression and its methylation in breast cancer patients. Overall, the goal of this report is to establish a strong clinical basis for further investigation into the cellular, molecular, and physiological roles of NISCH in BCa. Ultimately, NISCH gene expression might be clinically harnessed as a biomarker or predictor of invasiveness and metastasis in BCa.

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Fig. 1: Signaling pathways regulated by Nischarin.
Fig. 2: Mutation diagram for NISCH gene (exons) and protein from The Cancer Genome Atlas (TCGA) extracted from cBioPortal (https://www.cbioportal.org).
Fig. 3: Nischarin expression is associated with tumor subtype, grade, stage, size and DNA methylation status in breast cancer patients.
Fig. 4: Correlation analysis between NISCH and other genes.

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References

  1. Alahari SK, Lee JW, Juliano RL. Nischarin, a novel protein that interacts with the integrin α5 subunit and inhibits cell migration. J Cell Biol. 2000;151:1141–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maziveyi M, Alahari SK. Breast cancer tumor suppressors: a special emphasis on novel protein nischarin. Cancer Res. 2015;75:4252–9.

    Article  CAS  PubMed  Google Scholar 

  3. Baranwal S, Wang Y, Rathinam R, Lee J, Jin L, McGoey R, et al. Molecular characterization of the tumor-suppressive function of nischarin in breast cancer. J Natl Cancer Inst. 2011;103:1513–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jain P, Baranwal S, Dong S, Struckhoff AP, Worthylake RA, Alahari SK. Integrin-binding protein nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration of breast epithelial cells. J Biol Chem. 2013;288:15495–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ding Y, Zhang R, Zhang K, Lv X, Chen Y, Li A, et al. Nischarin is differentially expressed in rat brain and regulates neuronal migration. PLoS ONE. 2013;8:e54563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ding Y, Li Y, Lu L, Zhang R, Zeng L, Wang L, et al. Inhibition of nischarin expression promotes neurite outgrowth through regulation of PAK activity. PLoS ONE. 2015;10:e0144948.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Maziveyi M, Dong S, Baranwal S, Mehrnezhad A, Rathinam R, Huckaba TM, et al. Exosomes from nischarin-expressing cells reduce breast cancer cell motility and tumor growth. Cancer Res. 2019;79:2152–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McAndrews KM, Kalluri R. Nischarin regulates secretion of exosomes and cancer progression. Cancer Res. 2019;79:2099–101.

    Article  CAS  PubMed  Google Scholar 

  9. Cai Y-J, Ma B, Wang M-L, Chen J, Zhao F-G, Zhou J-D, et al. Impact of Nischarin on EMT regulators in breast cancer cell lines. Oncol Lett. 2020;20:1–1.

    Article  Google Scholar 

  10. Dong S, Ruiz‐Calderon B, Rathinam R, Eastlack S, Maziveyi M, Alahari SK. Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment. Int J cancer. 2020;146:2576–87.

    Article  CAS  PubMed  Google Scholar 

  11. Maziveyi M, Dong S, Baranwal S, Alahari SK. Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells. Mol cancer. 2018;17:1–11.

    Article  CAS  Google Scholar 

  12. Eastlack SC, Dong S, Mo YY, Alahari SK. Expression of long noncoding RNA MALAT1 correlates with increased levels of Nischarin and inhibits oncogenic cell functions in breast cancer. PLoS ONE. 2018;13:e0198945.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Guo Z, Yuan Y, Guo Y, Wang H, Song C, Huang M. Nischarin attenuates apoptosis induced by oxidative stress in PC12 cells. Exp therapeutic Med. 2019;17:663–70.

    CAS  Google Scholar 

  14. Ding Y, Milosavljevic T, Alahari SK. Nischarin inhibits LIM kinase to regulate cofilin phosphorylation and cell invasion. Mol Cell Biol. 2008;28:3742–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chang C, Wei W, Han D, Meng J, Zhu F, Xiao Y, et al. Expression of Nischarin negatively correlates with estrogen receptor and alters apoptosis, migration and invasion in human breast cancer. Biochemical biophysical Res Commun. 2017;484:536–42.

    Article  CAS  Google Scholar 

  16. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: a cancer J clinicians. 2021;71:7–33.

    Google Scholar 

  17. Tsang J, Tse GM. Molecular classification of breast cancer. Adv Anat Pathol. 2020;27:27–35.

    Article  CAS  PubMed  Google Scholar 

  18. Nagini S. Breast cancer: current molecular therapeutic targets and new players. Anti-Cancer Agents Medicinal Chem (Former Curr Medicinal Chem-Anti-Cancer Agents). 2017;17:152–63.

    CAS  Google Scholar 

  19. Piletz JE, Jones JC, Zhu H, Bishara O, Ernsberger P. Imidazoline receptor antisera-selected cDNA clone and mRNA distribution. Ann N. Y Acad Sci. 1999;881:1–7.

    Article  CAS  PubMed  Google Scholar 

  20. Ostrow KL, Hoque MO, Loyo M, Brait M, Greenberg A, Siegfried JM, et al. Molecular analysis of plasma DNA for the early detection of lung cancer by quantitative methylation-specific PCR. Clin Cancer Res. 2010;16:3463–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lim KP, Hong W. Human Nischarin/imidazoline receptor antisera-selected protein is targeted to the endosomes by a combined action of a PX domain and a coiled-coil region. J Biol Chem. 2004;279:54770–82.

    Article  CAS  PubMed  Google Scholar 

  22. Kuijl C, Pilli M, Alahari SK, Janssen H, Khoo PS, Ervin KE, et al. Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria. EMBO J. 2013;32:713–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jin L, Wessely O, Marcusson EG, Ivan C, Calin GA, Alahari SK. Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-α in breast cancer. Cancer Res. 2013;73:2884–96.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang L, Zhao TY, Hou N, Teng Y, Cheng X, Wang B, et al. Generation and primary phenotypes of imidazoline receptor antisera-selected (IRAS) knockout mice. CNS Neurosci Ther. 2013;19:978–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li F, Wu N, Su R, Chen Y, Lu X, Liu Y, et al. Imidazoline receptor antisera-selected/Nischarin regulates the effect of agmatine on the development of morphine dependence. Addict Biol. 2012;17:392–408.

    Article  CAS  PubMed  Google Scholar 

  26. Crompton M, Purnell T, Tyrer HE, Parker A, Ball G, Hardisty-Hughes RE, et al. A mutation in Nischarin causes otitis media via LIMK1 and NF-kappaB pathways. PLoS Genet. 2017;13:e1006969.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Dong S, Baranwal S, Garcia A, Serrano-Gomez SJ, Eastlack S, Iwakuma T, et al. Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. J Biol Chem. 2017;292:16833–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dong S, Bluher M, Zhang Y, Wu H, Alahari SK. Development of insulin resistance in Nischarin mutant female mice. Int J Obes (Lond). 2019;43:1046–57.

    Article  CAS  Google Scholar 

  29. Chen J, Feng WL, Mo WJ, Ding XW, Xie SN. Expression of integrin-binding protein Nischarin in metastatic breast cancer. Mol Med Rep. 2015;12:77–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li J, He X, Dong R, Wang Y, Yu J, Qiu H. Frequent loss of NISCH promotes tumor proliferation and invasion in ovarian cancer via inhibiting the FAK signal pathway. Mol Cancer Ther. 2015;14:1202–12.

    Article  CAS  PubMed  Google Scholar 

  31. Zhao Y, Liang X, Zhu F, Wen Y, Xu J, Yang J, et al. A large-scale integrative analysis of GWAS and common meQTLs across whole life course identifies genes, pathways and tissue/cell types for three major psychiatric disorders. Neurosci Biobehav Rev. 2018;95:347–52.

    Article  CAS  PubMed  Google Scholar 

  32. Rathnam C, Lee S, Jiang X. An algorithm for direct causal learning of influences on patient outcomes. Artif Intell Med. 2017;75:1–15.

    Article  PubMed  Google Scholar 

  33. Geng R, Wang Q, Chen E, Zheng QY. Current understanding of host genetics of otitis media. Front Genet. 2019;10:1395.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang J, Abdel-Rahman AA. Inhibition of nischarin expression attenuates rilmenidine-evoked hypotension and phosphorylated extracellular signal-regulated kinase 1/2 production in the rostral ventrolateral medulla of rats. J Pharm Exp Ther. 2008;324:72–78.

    Article  CAS  Google Scholar 

  35. Wu N, Su RB, Liu Y, Lu XQ, Zheng JQ, Cong B, et al. Modulation of agmatine on calcium signal in morphine-dependent CHO cells by activation of IRAS, a candidate for imidazoline I1 receptor. Eur J Pharm. 2006;548:21–28.

    Article  CAS  Google Scholar 

  36. Li F, Wu N, Su RB, Zheng JQ, Xu B, Lu XQ, et al. Involvement of phosphatidylcholine-selective phospholipase C in activation of mitogen-activated protein kinase pathways in imidazoline receptor antisera-selected protein. J Cell Biochem. 2006;98:1615–28.

    Article  CAS  PubMed  Google Scholar 

  37. Chen MJ, Zhu HE, Piletz JE. Intracellular effect of imidazoline receptor on alpha(2A)-noradrenergic receptor. Ann N. Y Acad Sci. 2003;1009:427–38.

    Article  CAS  PubMed  Google Scholar 

  38. Li S, Wu N, Zhao TY, Lu GY, Wang ZY, Li F, et al. The role of IRAS/Nischarin involved in the development of morphine tolerance and physical dependence. Biochem Biophys Res Commun. 2019;512:460–6.

    Article  CAS  PubMed  Google Scholar 

  39. Li F, Ma H, Wu N, Li J. IRAS modulates opioid tolerance and dependence by regulating mu opioid receptor trafficking. Mol Neurobiol. 2016;53:4918–30.

    Article  CAS  PubMed  Google Scholar 

  40. Amisten S, Duner P, Asplund O, Mohammed Al-Amily I, Groop L, Salehi A. Activation of imidazoline receptor I2, and improved pancreatic beta-cell function in human islets. J Diabetes Complications. 2018;32:813–8.

    Article  PubMed  Google Scholar 

  41. Lin MH, Hsu CC, Lin J, Cheng JT, Wu MC. Investigation of morin-induced insulin secretion in cultured pancreatic cells. Clin Exp Pharm Physiol. 2017;44:1254–62.

    Article  CAS  Google Scholar 

  42. Hotta K, Kitamoto A, Kitamoto T, Mizusawa S, Teranishi H, So R, et al. Replication study of 15 recently published Loci for body fat distribution in the Japanese population. J Atheroscler Thromb. 2013;20:336–50.

    Article  CAS  PubMed  Google Scholar 

  43. Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010;42:949–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Uren C, Henn BM, Franke A, Wittig M, van Helden PD, Hoal EG, et al. A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility. PLoS One. 2017;12:e0174738.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Keller B, Garcia-Sevilla JA. Effects of I2-imidazoline receptor (IR) alkylating BU99006 in the mouse brain: Upregulation of nischarin/I1-IR and mu-opioid receptor proteins and modulation of associated signalling pathways. Neurochem Int. 2017;108:169–76.

    Article  CAS  PubMed  Google Scholar 

  46. Nagakura Y, Ide R, Saiki C, Sato Hashizume N, Imai T. Expression of nischarin, an imidazoline 1 receptor candidate protein, in the ventrolateral medulla of newborn rats. Neurosci Lett. 2021;761:136113.

    Article  CAS  PubMed  Google Scholar 

  47. Wu X, Xu W, Cui G, Yan Y, Wu X, Li L, et al. The expression pattern of Nischarin after lipopolysaccharides (LPS)-induced neuroinflammation in rats brain cortex. Inflamm Res. 2013;62:929–40.

    Article  CAS  PubMed  Google Scholar 

  48. Keller B, Mestre-Pinto JI, Alvaro-Bartolome M, Martinez-Sanvisens D, Farre M, Garcia-Fuster MJ, et al. A biomarker to differentiate between primary and cocaine-induced major depression in cocaine use disorder: the role of platelet IRAS/Nischarin (I1-imidazoline receptor). Front Psychiatry. 2017;8:258.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Keller B, Garcia-Sevilla JA. Dysregulation of IRAS/nischarin and other potential I1-imidazoline receptors in major depression postmortem brain: downregulation of basal contents by antidepressant drug treatments. J Affect Disord. 2017;208:646–52.

    Article  CAS  PubMed  Google Scholar 

  50. Ding YM, Li YY, Wang C, Huang H, Zheng CC, Huang SH, et al. Nischarin-siRNA delivered by polyethylenimine-alginate nanoparticles accelerates motor function recovery after spinal cord injury. Neural Regen Res. 2017;12:1687–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E. PC12 Cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells. 2020;9:1–76.

    Article  CAS  Google Scholar 

  52. Guo Z, Huang M, Yuan Y, Guo Y, Song C, Wang H, et al. Nischarin downregulation attenuates cell injury induced by oxidative stress via Wnt signaling. Neuroreport. 2020;31:1199–207.

    Article  CAS  PubMed  Google Scholar 

  53. McGuire A, Brown JA, Malone C, McLaughlin R, Kerin MJ. Effects of age on the detection and management of breast cancer. Cancers. 2015;7:908–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004;6:91–99.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to thank the Fred G. Brazda Foundation and the Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine and Health Sciences Center, New Orleans, for their financial support.

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  1. These authors contributed equally: Samuel C. Okpechi, Hassan Yousefi.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Louisiana State University School of Medicine and Health Sciences Center, New Orleans, LA, USA

    Samuel C. Okpechi, Hassan Yousefi & Suresh K. Alahari

  2. Stanley S. Scott Cancer Center, Louisiana State University School of Medicine and Health Sciences Center, New Orleans, LA, USA

    Samuel C. Okpechi, Hassan Yousefi & Suresh K. Alahari

  3. Section of Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, LA, USA

    Khoa Nguyen, Thomas Cheng, Bridgette Collins-Burow & Matthew E. Burow

  4. Louisiana State University Biological Sciences, Baton Rouge, LA, USA

    Nikhilesh V. Alahari

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Contributions

SO wrote the first draft, HY did bioinformatic analysis and prepared figures, KN, NA, BB, MB contributed to the text, TC created some figures, and SKA finalized the text and figures.

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Correspondence to Suresh K. Alahari.

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Okpechi, S.C., Yousefi, H., Nguyen, K. et al. Role of Nischarin in the pathology of diseases: a special emphasis on breast cancer. Oncogene 41, 1079–1086 (2022). https://doi.org/10.1038/s41388-021-02150-4

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