Differential Expression of lincRNA-ROR Spliced Transcript Variants in Breast Cancer
-
Mozhgan Sadat Akhtar
,
Akram Gholipour
,
Mahrokh Bagheri Moghadam
,
Maziar Oveisee
,
Seyed Javad Mowla
,
Mahshid Malakootian
Abstract
Background: We investigated the expression pattern of a human stem cell-specific, large intergenic noncoding RNA (lincRNA) regulator of reprogramming (lincRNA-ROR) and its spliced transcript variants in breast tumors. Breast cancer is the leading cause of cancer mortality in women; therefore, finding a reliable diagnostic tumor marker, based on the molecular profile of tumor cells, is warranted.
Methods: qRT-PCR was used to investigate the expression alteration of a specific stem cell-related lincRNA and its spliced transcript variants in breast tumors which provided by the Iran National Tumor Bank (2014-2016). Suitability of lincRNA-ROR and expression alterations of its spliced transcript variants as breast tumor biomarkers were examined by ROC curve analysis.
Results: Expression was significantly upregulated in lincRNA-ROR variants 1 (NR-048536) and 4 (AB844432) and downregulated in variant 3 (AB844431), with expression levels failing to distinguish between breast tumor types, grades, and malignancy stages. Whereas ROC curve analysis gave good scores to the expressions of variants 1 (AUC=0.7675, P=0.003) and 3 (AUC=0.9383, P=0.00173), suggesting their suitability as potential breast tumor biomarkers, it gave an AUC score of 0.6033 for lincRNA-ROR spliced variant 4 (P=0.4118), denoting its unsuitability as a breast cancer biomarker.
Conclusion: Aberrant expressions of lincRNA-ROR spliced transcript variants could serve as reliable biomarkers with potential usefulness in breast cancer diagnosis. However, further research should elucidate the role and tissue expression of lincRNA-ROR spliced transcript variants in various cancers.
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11. Huang XJ, Xia Y, He GF, et al (2018). MALAT1 promotes angiogenesis of breast cancer. Oncol Rep, 40:2683-2689.
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13. Wang Y, Xu Z, Jiang J, et al (2013). Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell, 25:69-80.
14. Hou P, Zhao Y, Li Z, et al (2014). LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis, 5:e1287.
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16. Takahashi K, Yan IK, Kogure T, et al (2014). Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio, 4:458-467.
17. Yu X, Ding H, Shi Y, et al (2020). Downregulated Expression of linc-ROR in Gastric Cancer and Its Potential Diagnostic and Prognosis Value. Dis Markers, 2020: 7347298.
18. Li X, Chen W, Jia J, et al (2020). The long non-coding RNA-RoR promotes the tumorigenesis of human colorectal cancer by targeting miR-6833-3p through SMC4. Onco Targets Ther, 13:2573-2581.
19. Lou Y, Jiang H, Cui Z, et al (2017). Linc-ROR induces epithelial-to-mesenchymal transition in ovarian cancer by increasing Wnt/β-catenin signaling. Oncotarget, 8(41):69983-69994.
20. Chen W, Wang H, Liu Y, et al (2020). Linc‐RoR promotes proliferation, migration, and invasion via the Hippo/YAP pathway in pancreatic cancer cells. J Cell Biochem, 121:632-641.
21. Sahebi R, Malakootian M, Balalaee B, et al (2016). Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma. Iran J Basic Med Sci, 19(10):1131-1135.
22. Peng W-x, Huang J-g, Yang L, et al (2017). Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer, 16:161.
23. Chen Y-M, Liu Y, Wei H-Y, et al (2016). Linc-ROR induces epithelial-mesenchymal transition and contributes to drug resistance and invasion of breast cancer cells. Tumour Biol, 37:10861-10870.
24. Zhao T, Wu L, Li X, Dai H, Zhang Z (2017). Large intergenic non-coding RNA-ROR as a potential biomarker for the diagnosis and dynamic monitoring of breast cancer. Cancer Biomark, 20:165-173.
25. Mirzadeh Azad F, Taheri Bajgan E, Naeli P, et al (2022). Differential expression pattern of Linc-ROR spliced variants in pluripotent and nonpluripotent cell lines. Cell J, 24(10): 569-576.
26. Malakootian M, Mirzadeh Azad F, Fouani Y, et al (2018). Anti-differentiation non-coding RNA, ANCR, is differentially expressed in different types of brain tumors. J Neurooncol, 138:261-270.
27. Bhattacharyya N, Pandey V, Bhattacharyya M, Dey A (2021). Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: From novel biomarkers to promising therapeutic strategies. Asian J Pharm Sci, 16(5):533-550.
28. Wang Z, Zheng Y (2018). lncRNAs regulate innate immune responses and their roles in macrophage polarization. Mediators Inflamm, 2018: 8050956.
29. Pan Y, Li C, Chen J, Zhang K, Chu X, Wang R, Chen L (2016). The emerging roles of long noncoding RNA ROR (lincRNA-ROR) and its possible mechanisms in human cancers. Cell Physiol Biochem, 40:219-229.
30. Chen W, Yang J, Fang H, Li L, Sun J (2020). Relevance function of linc-ROR in the pathogenesis of cancer. Front Cell Dev Biol, 8:696.
31. Zhan H-x, Wang Y, Li C, et al (2016). LincRNA-ROR promotes invasion, metastasis and tumor growth in pancreatic cancer through activating ZEB1 pathway. Cancer Lett, 374:261-271.
32. Mi Y, Li Y, He Z, Chen D, Hong Q, You J (2021). Upregulation of Linc-ROR Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells Through miR-212-3p/FGF7 Axis. Cancer Manag Res, 13:899-912.
33. Zhang H-Y, Liang F, Zhang J-W, et al (2017). Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother Pharmacol, 79:327-337.
34. Gao S, Wang P, Hua Y, et al (2016). ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer. Oncotarget, 7:1608-18.
35. Malakootian M, Azad FM, Naeli P, et al (2017). Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. Eur J Cell Biol, 96:347-355.
36. Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW (2008). OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells, 26:3068-3074.
37. Zhou X, Gao Q, Wang J, et al (2014). Linc-RNA-RoR acts as a “sponge” against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. Gynecol Oncol, 133:333-339.
38. Taheri Bajgan E, Gholipour A, Faghihi M, et al (2022). Linc-ROR has a Potential ceRNA Activity for OCT4A by Sequestering miR-335-5p in the HEK293T Cell Line. Biochem Genet, 60(3):1007-1024.
39. Hou L, Tu J, Cheng F, et al (2018). Long noncoding RNA ROR promotes breast cancer by regulating the TGF-β pathway. Cancer Cell Int, 18:142.
40. Luo C, Cao J, Peng R, et al (2018). Functional variants in linc-ROR are associated with mRNA expression of LINC-ROR and breast cancer susceptibility. Sci Rep, 8:4680.
41. Meseure D, Vacher S, Lallemand F, et al (2016). Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer. Br J Cancer, 114:1395-1404.
42. Arun G, Aggarwal D, Spector DL (2020). MALAT1 long non-coding RNA: Functional implications. Noncoding RNA, 6:22.
43. Mirzadeh Azad F, Malakootian M, Mowla SJ (2019). The Regulatory Effect of lncRNA PSORS1C3 on Different Variants of OCT4 in non-Pluripotent Cells. J Cell Mol Res, 11:8-13.
44. Chen J, Weiss W (2015). Alternative splicing in cancer: implications for biology and therapy. Oncogene, 34:1-14.
45. Wu S, Nitschke K, Worst TS, et al (2020). Long noncoding RNA MIR31HG and its splice variants regulate proliferation and migration: prognostic implications for muscle invasive bladder cancer. J Exp Clin Cancer Res, 39:288.
46. Yang T, Zhou H, Liu P, et al (2017). lncRNA PVT1 and its splicing variant function as competing endogenous RNA to regulate clear cell renal cell carcinoma progression. Oncotarget, 8: 85353-85367.
47. Azad FM, Malakootian M, Mowla SJ (2019). lncRNA PSORS1C3 is regulated by glucocorticoids and fine-tunes OCT4 expression in non-pluripotent cells. Sci Rep, 9:8370.
48. Hartwell L, Mankoff D, Paulovich A, et al (2006). Cancer biomarkers: a systems approach. Nat Biotechnol, 24:905-908.
2. Ferlay J, Soerjomataram I, Dikshit R, et al (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 136:E359-E386.
3. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B (2015). Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res, 5:2929-43.
4. Fehm TN, Stickeler E, Fasching PA, et al (2021). Update Breast Cancer 2021 Part 3 - Current Developments in the Treatment of Early Breast Cancer: Review and Assessment of Specialised Treatment Scenarios by an International Expert Panel. Geburtshilfe Frauenheilkd, 81:654-665.
5. Liang Y, Song X, Li Y, Chen B, et al (2020). LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer, 19:85.
6. Soudyab M, Iranpour M, Ghafouri-Fard S (2016). The role of long non-coding RNAs in breast cancer. Arch Iran Med, 19(7):508-17.
7. Gao N, Li Y, Li J, et al (2020). Long Non-Coding RNAs: the regulatory mechanisms, research strategies, and future directions in cancers. Front Oncol, 10: 598817.
8. Statello L, Guo C-J, Chen L-L, Huarte M (2021). Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol, 22:96-118.
9. Eades G, Wolfson B, Zhang Y, et al (2015). lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res, 13:330-338.
10. Cantile M, Di Bonito M, Cerrone M, Collina F, De Laurentiis M, Botti G (2020). Long non-coding RNA HOTAIR in breast cancer therapy. Cancers (Basel), 12:1197.
11. Huang XJ, Xia Y, He GF, et al (2018). MALAT1 promotes angiogenesis of breast cancer. Oncol Rep, 40:2683-2689.
12. Loewer S, Cabili MN, Guttman M, et al (2010). Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet, 42:1113-1117.
13. Wang Y, Xu Z, Jiang J, et al (2013). Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell, 25:69-80.
14. Hou P, Zhao Y, Li Z, et al (2014). LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis, 5:e1287.
15. Jiang X, Zhang G, Wu J, et al (2020). Long Noncoding RNA Serve as a Potential Predictive Biomarker for Breast Cancer: A Meta-Analysis. Biomed Res Int, 2020: 9045786.
16. Takahashi K, Yan IK, Kogure T, et al (2014). Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio, 4:458-467.
17. Yu X, Ding H, Shi Y, et al (2020). Downregulated Expression of linc-ROR in Gastric Cancer and Its Potential Diagnostic and Prognosis Value. Dis Markers, 2020: 7347298.
18. Li X, Chen W, Jia J, et al (2020). The long non-coding RNA-RoR promotes the tumorigenesis of human colorectal cancer by targeting miR-6833-3p through SMC4. Onco Targets Ther, 13:2573-2581.
19. Lou Y, Jiang H, Cui Z, et al (2017). Linc-ROR induces epithelial-to-mesenchymal transition in ovarian cancer by increasing Wnt/β-catenin signaling. Oncotarget, 8(41):69983-69994.
20. Chen W, Wang H, Liu Y, et al (2020). Linc‐RoR promotes proliferation, migration, and invasion via the Hippo/YAP pathway in pancreatic cancer cells. J Cell Biochem, 121:632-641.
21. Sahebi R, Malakootian M, Balalaee B, et al (2016). Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma. Iran J Basic Med Sci, 19(10):1131-1135.
22. Peng W-x, Huang J-g, Yang L, et al (2017). Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer, 16:161.
23. Chen Y-M, Liu Y, Wei H-Y, et al (2016). Linc-ROR induces epithelial-mesenchymal transition and contributes to drug resistance and invasion of breast cancer cells. Tumour Biol, 37:10861-10870.
24. Zhao T, Wu L, Li X, Dai H, Zhang Z (2017). Large intergenic non-coding RNA-ROR as a potential biomarker for the diagnosis and dynamic monitoring of breast cancer. Cancer Biomark, 20:165-173.
25. Mirzadeh Azad F, Taheri Bajgan E, Naeli P, et al (2022). Differential expression pattern of Linc-ROR spliced variants in pluripotent and nonpluripotent cell lines. Cell J, 24(10): 569-576.
26. Malakootian M, Mirzadeh Azad F, Fouani Y, et al (2018). Anti-differentiation non-coding RNA, ANCR, is differentially expressed in different types of brain tumors. J Neurooncol, 138:261-270.
27. Bhattacharyya N, Pandey V, Bhattacharyya M, Dey A (2021). Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: From novel biomarkers to promising therapeutic strategies. Asian J Pharm Sci, 16(5):533-550.
28. Wang Z, Zheng Y (2018). lncRNAs regulate innate immune responses and their roles in macrophage polarization. Mediators Inflamm, 2018: 8050956.
29. Pan Y, Li C, Chen J, Zhang K, Chu X, Wang R, Chen L (2016). The emerging roles of long noncoding RNA ROR (lincRNA-ROR) and its possible mechanisms in human cancers. Cell Physiol Biochem, 40:219-229.
30. Chen W, Yang J, Fang H, Li L, Sun J (2020). Relevance function of linc-ROR in the pathogenesis of cancer. Front Cell Dev Biol, 8:696.
31. Zhan H-x, Wang Y, Li C, et al (2016). LincRNA-ROR promotes invasion, metastasis and tumor growth in pancreatic cancer through activating ZEB1 pathway. Cancer Lett, 374:261-271.
32. Mi Y, Li Y, He Z, Chen D, Hong Q, You J (2021). Upregulation of Linc-ROR Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells Through miR-212-3p/FGF7 Axis. Cancer Manag Res, 13:899-912.
33. Zhang H-Y, Liang F, Zhang J-W, et al (2017). Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother Pharmacol, 79:327-337.
34. Gao S, Wang P, Hua Y, et al (2016). ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer. Oncotarget, 7:1608-18.
35. Malakootian M, Azad FM, Naeli P, et al (2017). Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. Eur J Cell Biol, 96:347-355.
36. Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW (2008). OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells, 26:3068-3074.
37. Zhou X, Gao Q, Wang J, et al (2014). Linc-RNA-RoR acts as a “sponge” against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. Gynecol Oncol, 133:333-339.
38. Taheri Bajgan E, Gholipour A, Faghihi M, et al (2022). Linc-ROR has a Potential ceRNA Activity for OCT4A by Sequestering miR-335-5p in the HEK293T Cell Line. Biochem Genet, 60(3):1007-1024.
39. Hou L, Tu J, Cheng F, et al (2018). Long noncoding RNA ROR promotes breast cancer by regulating the TGF-β pathway. Cancer Cell Int, 18:142.
40. Luo C, Cao J, Peng R, et al (2018). Functional variants in linc-ROR are associated with mRNA expression of LINC-ROR and breast cancer susceptibility. Sci Rep, 8:4680.
41. Meseure D, Vacher S, Lallemand F, et al (2016). Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer. Br J Cancer, 114:1395-1404.
42. Arun G, Aggarwal D, Spector DL (2020). MALAT1 long non-coding RNA: Functional implications. Noncoding RNA, 6:22.
43. Mirzadeh Azad F, Malakootian M, Mowla SJ (2019). The Regulatory Effect of lncRNA PSORS1C3 on Different Variants of OCT4 in non-Pluripotent Cells. J Cell Mol Res, 11:8-13.
44. Chen J, Weiss W (2015). Alternative splicing in cancer: implications for biology and therapy. Oncogene, 34:1-14.
45. Wu S, Nitschke K, Worst TS, et al (2020). Long noncoding RNA MIR31HG and its splice variants regulate proliferation and migration: prognostic implications for muscle invasive bladder cancer. J Exp Clin Cancer Res, 39:288.
46. Yang T, Zhou H, Liu P, et al (2017). lncRNA PVT1 and its splicing variant function as competing endogenous RNA to regulate clear cell renal cell carcinoma progression. Oncotarget, 8: 85353-85367.
47. Azad FM, Malakootian M, Mowla SJ (2019). lncRNA PSORS1C3 is regulated by glucocorticoids and fine-tunes OCT4 expression in non-pluripotent cells. Sci Rep, 9:8370.
48. Hartwell L, Mankoff D, Paulovich A, et al (2006). Cancer biomarkers: a systems approach. Nat Biotechnol, 24:905-908.
| Files | ||
| Issue | Vol 52 No 2 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i2.11896 | |
| Keywords | ||
| Spliced variants Breast tumor tissues | ||
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How to Cite
1.
Sadat Akhtar M, Gholipour A, Bagheri Moghadam M, Oveisee M, Mowla SJ, Malakootian M. Differential Expression of lincRNA-ROR Spliced Transcript Variants in Breast Cancer. Iran J Public Health. 2023;52(2):427-435.
