Ferdowsi University of Mashhad

Document Type : Research Articles

Authors

1 Tarbiat Modares University, Tehran, Iran

2 Iran University of Medical Sciences, Tehran, Iran

Abstract

OCT4 is the major regulator of pluripotency in embryonic stem cells and its association with tumorigenesis, cellular stress response, and homeostatic multifactorial diseases have been recently reported. To serve the versatility in its function, OCT4 generates several transcript variants which their expression levels are tightly regulated through different mechanisms. PSORS1C3 is a long non-coding RNA with overlapping genomic location with OCT4 gene. Here, we investigated the effect of PSORS1C3 overexpression on OCT4 expression in different cell lines. Our data revealed that ectopic expression of PSORS1C3 did not affect OCT4 transcripts abundance in NT2 cells, as a model of pluripotent cells. However, in HEK293T cells, PSORS1C3 overexpression led to an increase in OCT4B as a homeostatic isoform and a decrease in OCT4A transcript level. We also observed that manipulating PSORS1C3 in HeLa cells, as a model of epithelial carcinoma line, caused an upregulation in OCT4A, OCT4C which could regulate stemness and proliferation and OCT4B transcripts at different time points. Our findings indicated that PSORS1C3 could affect the expression level of OCT4 spliced variants, according to their functions and the cells molecular context as well as genetic background. Considering these diverse regulatory effects and co-expression of OCT4 and PSORS1C3 in some cell lines, it is safe to consider PSORS1C3 as a modulator of OCT4 expression in non-pluripotent cells and in association with homeostatic pathways.

Keywords

Arvey A., Agius P., Noble W.S. and Leslie C. (2012) Sequence and chromatin determinants of cell-type-specific transcription factor binding. Genome research 22: 1723-1734.
Asadi M.H., Mowla S.J., Fathi F., Aleyasin A., Asadzadeh J. and Atlasi Y. (2011) OCT4B1, a novel spliced variant of OCT4, is highly expressed in gastric cancer and acts as an antiapoptotic factor. International Journal of Cancer 128: 2645-2652.
Atlasi Y., Mowla S.J., Ziaee S.A. and Bahrami A.R. (2007) OCT‐4, an embryonic stem cell marker, is highly expressed in bladder cancer. International Journal of Cancer 120: 1598-1602.
Atlasi Y., Mowla S.J., Ziaee S.A., Gokhale P.J. and Andrews P.W. (2008) OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells 26: 3068-3074.
Bai M., Yuan M., Liao H., Chen J., Xie B., Yan D., Xi X., Xu X., Zhang Z. and Feng Y. (2015) OCT4 pseudogene 5 upregulates OCT4 expression to promote proliferation by competing with miR-145 in endometrial carcinoma. Oncology reports 33: 1745-1752.
Bhat S.A., Ahmad S.M., Mumtaz P.T., Malik A.A., Dar M.A., Urwat U., Shah R.A. and Ganai N.A. (2016) Long non-coding RNAs: Mechanism of action and functional utility. Noncoding RNA Res 1: 43-50.
Campbell P.A., Perez-Iratxeta C., Andrade-Navarro M.A. and Rudnicki M.A. (2007) Oct4 targets regulatory nodes to modulate stem cell function. PLoS One 2: 553-564.
Chang Y.T., Hsu C.Y., Chou C.T., Lin M.W., Shiao Y.M., Tsai C.Y., Yu C.W., Shiue J.J., Lee Y.F., Huang C.H., Chen C.C., Lee D.D., Wang W.J., Liu H.N. and Tsai S.F. (2007) The genetic polymorphisms of POU5F1 gene are associated with psoriasis vulgaris in Chinese. J Dermatol Sci 46: 153-156.
Cortes-Dericks L., Yazd E.F., Mowla S.J., Schmid R.A. and Karoubi G. (2013) Suppression of OCT4B enhances sensitivity of lung adenocarcinoma A549 cells to cisplatin via increased apoptosis. Anticancer Res 33: 5365-5373.
Du Z., Jia D., Liu S., Wang F., Li G., Zhang Y., Cao X., Ling E.A. and Hao A. (2009) Oct4 is expressed in human gliomas and promotes colony formation in glioma cells. Glia 57: 724-733.
Engreitz J.M., Haines J.E., Perez E.M., Munson G., Chen J., Kane M., Mcdonel P.E., Guttman M. and Lander E.S. (2016) Local regulation of gene expression by lncRNA promoters, transcription and splicing. Nature 539: 452-455.
Farashahi Yazd E., Rafiee M.R., Soleimani M., Tavallaei M., Salmani M.K. and Mowla S.J. (2011) OCT4B1, a novel spliced variant of OCT4, generates a stable truncated protein with a potential role in stress response. Cancer Lett 309: 170-175.
Gao Y., Wang X., Han J., Xiao Z., Chen B., Su G. and Dai J. (2010) The novel OCT4 spliced variant OCT4B1 can generate three protein isoforms by alternative splicing into OCT4B. Journal of Genetics and Genomics 37: 461-465.
Gao Y., Wei J., Han J., Wang X., Su G., Zhao Y., Chen B., Xiao Z., Cao J. and Dai J. (2012) The novel function of OCT4B isoform-265 in genotoxic stress. Stem Cells 30: 665-672.
Holm S., Sanchez F., Carlen L., Mallbris L., Ståhle M. and O'brien K. (2005) HLA-Cw 0602 Associates More Strongly to Psoriasis in the Swedish Population than Variants of the Novel 6p21. 3 Gene PSORS1C3. Acta dermato-venereologica 85: 2-8
Kelly G.M. and Gatie M.I. (2017) Mechanisms Regulating Stemness and Differentiation in Embryonal Carcinoma Cells. Stem Cells International 2017: 20-40.
Li D., Yang Z.K., Bu J.Y., Xu C.Y., Sun H., Tang J.B., Lin P., Cheng W., Huang N., Cui R.J., Yu X.G. and Zheng X.L. (2015) OCT4B modulates OCT4A expression as ceRNA in tumor cells. Oncol Rep 33: 2622-2630.
Lin S.C., Chung C.H., Chung C.H., Kuo M.H., Hsieh C.H., Chiu Y.F., Shieh Y.S., Chou Y.T. and Wu C.W. (2019) OCT4B mediates hypoxia-induced cancer dissemination. Oncogene 38: 1093-1105.
Lin Y., Ding C., Zhang K., Ni B., Da M., Hu L., Hu Y., Xu J., Wang X., Chen Y., Mo X., Cui Y., Shen H., Sha J., Liu J. and Hu Z. (2015) Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese. Scientific reports 5: 15860-15860.
Malakootian M., Mirzadeh Azad F., Naeli P., Pakzad M., Fouani Y., Taheri Bajgan E., Baharvand H. and Mowla S.J. (2017) Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. European Journal of Cell Biology 96: 347-355
Maragkoudaki M., Vaiopoulou A., Theodoropoulos G.E., Legaki E., Sechi L.A., Karamanolis G., Zografos G. and Gazouli M. (2015) Specific detection of OCT4 isoforms in inflammatory bowel disease. Gut pathogens 7: 25-25.
Meng L., Hu H., Zhi H., Liu Y., Shi F., Zhang L., Zhou Y. and Lin A. (2018) OCT4B regulates p53 and p16 pathway genes to prevent apoptosis of breast cancer cells. Oncology letters 16: 522-528.
Murphy T.M., Crawford B., Dempster E.L., Hannon E., Burrage J., Turecki G., Kaminsky Z. and Mill J. (2017) Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide. Transl Psychiatry 7: 989-998.
Nakagawa S. (2016) Lessons from reverse-genetic studies of lncRNAs. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1859: 177-183.
Rijlaarsdam M.A., Van Herk H.a.D.M., Gillis A.J.M., Stoop H., Jenster G., Martens J., Van Leenders G.J.L.H., Dinjens W., Hoogland A.M., Timmermans M. and Looijenga L.H.J. (2011) Specific detection of OCT3/4 isoform A/B/B1 expression in solid (germ cell) tumours and cell lines: confirmation of OCT3/4 specificity for germ cell tumours. British Journal Of Cancer 105:854-863.
Schor I.E., Bussotti G., Maleš M., Forneris M., Viales R.R., Enright A.J. and Furlong E.E.M. (2018) Non-coding RNA Expression, Function, and Variation during Drosophila Embryogenesis. Current Biology 28: 3547-3561.
Shi Y., Ye P. and Long X. (2017) Differential Expression Profiles of the Transcriptome in Breast Cancer Cell Lines Revealed by Next Generation Sequencing. Cellular Physiology and Biochemistry 44: 804-816.
Stepanenko A.A. and Dmitrenko V.V. (2015) HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution. Gene 569: 182-190.
Wang X. and Dai J. (2010) Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem cells 28: 885-893.
Wang Y., Xu Z., Jiang J., Xu C., Kang J., Xiao L., Wu M., Xiong J., Guo X. and Liu H. (2013) Endogenous miRNA Sponge lincRNA-RoR Regulates Oct4, Nanog, and Sox2 in Human Embryonic Stem Cell Self-Renewal. Developmental Cell 25: 69-80.
Wang Y.D., Cai N., Wu X.L., Cao H.Z., Xie L.L. and Zheng P.S. (2013) OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death & Disease 4: 760-770.
Zhao R., Deibler R.W., Lerou P.H., Ballabeni A., Heffner G.C., Cahan P., Unternaehrer J.J., Kirschner M.W. and Daley G.Q. (2014) A nontranscriptional role for Oct4 in the regulation of mitotic entry. Proceedings of the National Academy of Sciences 111: 15768-15773
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