Top

Published in:

01-12-2016 | Laboratory Investigation

OCT4 spliced variants are highly expressed in brain cancer tissues and inhibition of OCT4B1 causes G2/M arrest in brain cancer cells

Authors: Malek Hossein Asadi, Khosrow Khalifeh, Seyed Javad Mowla

Published in: Journal of Neuro-Oncology | Issue 3/2016

Abstract

The new claim about the origin of cancer known as Cancer Stem Cell theory states that a somatic differentiated cell can dedifferentiated or reprogrammed for regaining the cancer cell features. It has been recently shown that expression of stemness factors such as Oct4, Sox2, Nanog and Klf4, in a variety of somatic cancers can leads to development of tumorogenesis. Here, the expression of Oct4 variants were evaluated in brain tumor tissues by quantitative RT-PCR and immunohistochemical (IHC) analysis. In next phase of our study, the expression of Oct4B1 was knock-down in brain cancer cell lines and its effect on cell cycle was assessed. Finally, in order to get insights into sequence-structure-function relationships of Oct4 isofroms, their sequences were analysed using bioinformatic tools. Our data revealed that all three variants of Oct4 are expressed in different types of brain cancer. The expression level of Oct4B1, in contast to Oct4B, was much higher in high-grade brain tumors compared with low-grade ones. In line with qPCR, the expression of Oct4A and B isofroms was confirmed with IHC in different types of brain tumors. Moreover, as a result of the suppression of Oct4B1 expression, the brain cancer cells were arrested in G2/M phase of cell cycle. Bioinfromatics data indicated that the predicted Oct4B1 protein have DNA binding properties. All together, our findings suggest that Oct4B1 has a potential role in tumorigenesis of brain cancer and can be considered as a new tumor marker with potential value in diagnosis and treatment of brain cancer.

Al-Hajj M, Clarke MF (2004) Self-renewal and solid tumor stem cells. Oncogene 23:7274–7282CrossRefPubMed

Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124:1111–1115CrossRefPubMed

Cao L, Li C, Shen S, Yan Y, Ji W, Wang J, Qian H, Jiang X, Li Z, Wu M (2013) OCT4 increases BIRC5 and CCND1 expression and promotes cancer progression in hepatocellular carcinoma. BMC Cancer 13:82CrossRefPubMedPubMedCentral

Wen J, Park JY, Park KH, Chung HW, Bang S, Park SW, Song SY (2010) Oct4 and Nanog expression is associated with early stages of pancreatic carcinogenesis. Pancreas 39:622–626CrossRefPubMed

Asadi MH, Derakhshani A, Mowla SJ (2014) Concomitant upregulation of nucleostemin and downregulation of Sox2 and Klf4 in gastric adenocarcinoma. Tumour Biol 35:7177–7185CrossRefPubMed

Rothenberg ME, Clarke MF, Diehn M (2010) The Myc connection: ES cells and cancer. Cell 143:184–186CrossRefPubMed

Clarissa NA, Brad AB (2015) Enrichment of the embryonic stem cell reprogramming factors Oct4, Nanog, Myc, and Sox2 in benign and malignant vascular tumors. BMC Clin Pathol 15:18CrossRef

Radzisheuskaya A, Silva JC (2014) Do all roads lead to Oct4? the emerging concepts of induced pluripotency. Trends Cell Biol 24:275–284CrossRefPubMedPubMedCentral

Tsai CC, Su PF, Huang YF, Yew TL, Hung SC (2012) Oct4 and Nanog directly regulate Dnmt1 to maintain self-renewal and undifferentiated state in mesenchymal stem cells. Mol Cell 47:169–182CrossRefPubMed

10.

Bouillez A, Rajabi H, Pitroda S, Jin C, Alam M, Kharbanda A, Tagde A, Wong KK, Kufe D (2016) Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res 76:1538–1548CrossRefPubMed

11.

Tagde A, Rajabi H, Bouillez A, Alam M, Gali R, Bailey S, Tai YT, Hideshima T, Anderson K, Avigan D, Kufe D (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587–2597CrossRefPubMed

12.

Rajabi H, Tagde A, Alam M, Bouillez A, Pitroda S, Suzuki Y, Kufe D (2016) DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene. doi:10.1038/onc.2016.180 PubMed

13.

Tagde A, Rajabi H, Stroopinsky D, Gali R, Alam M, Bouillez A, Kharbanda S, Stone R, Avigan D, Kufe D (2016) MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget 7:38974–38987PubMed

14.

Nath S, Mukherjee P (2014) MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med 20:332–342CrossRefPubMed

15.

Takahashi H, Jin C, Rajabi H, Pitroda S, Alam M, Ahmad R, Raina D, Hasegawa M, Suzuki Y, Tagde A, Bronson RT, Weichselbaum R, Kufe D (2015) MUC1-C activates the TAK1 inflammatory pathway in colon cancer. Oncogene 34:5187–5197CrossRefPubMedPubMedCentral

16.

Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, Tagde A, Maeda T, Hiraki M, Sukhatme VP, Kufe D (2016) Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget 7:11756–11769PubMedPubMedCentral

17.

Lopez-Bertoni H, Lal B, Li A, Caplan M, Guerrero-Cázares H, Eberhart CG, Quiñones-Hinojosa A, Glas M, Scheffler B, Laterra J, Li Y (2015) DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34:3994–4004CrossRefPubMed

18.

Takeda J, Seino S, Bell GI (1992) Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues. Nucleic Acids Res 20:4613–4620CrossRefPubMedPubMedCentral

19.

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 26:3068–3074CrossRefPubMed

20.

Asadi MH, Mowla SJ, Fathi F, Aleyasin A, Asadzadeh J, Atlasi Y (2011) OCT4B1, a novel spliced variant of OCT4, is highly expressed in gastric cancer and acts as an antiapoptotic factor. Int J Cancer 128:2645–2652CrossRefPubMed

21.

Asadzadeh J, Asadi MH, Shakhssalim N, Rafiee MR, Kalhor HR, Tavallaei M, Mowla SJ (2012) A plausible anti-apoptotic role of up-regulated OCT4B1 in bladder tumors. Urol J 9:574–580PubMed

22.

Mirzaei MR, Najafi A, Arababadi MK, Asadi MH, Mowla SJ (2014) Altered expression of apoptotic genes in response to OCT4B1 suppression in human tumor cell lines. Tumour Biol 35:9999–10009CrossRefPubMed

23.

Mirzaei MR, Kazemi Arababadi M, Asadi MH, Mowla SJ (2016) Altered expression of high molecular weight heat shock proteins after OCT4B1 suppression in human tumor cell lines. Cell J 17:608–616PubMedPubMedCentral

24.

Mirzaei MR, Asadi MH, Mowla SJ, Hassanshahi G, Ahmadi Z (2016) Down-regulation of HSP40 gene family following OCT4B1 suppression in human tumor cell lines. Iran J Basic Med Sci 19:187–193PubMedPubMedCentral

25.

Farashahi Yazd E, Rafiee MR, Soleimani M, Tavallaei M, Salmani MK, Mowla SJ (2011) OCT4B1, a novel spliced variant of OCT4, generates a stable truncated protein with a potential role in stress response. Cancer Lett 309:170–175CrossRefPubMed

26.

Sonawane P, Cho HE, Tagde A, Verlekar D, Yu AL, Reynolds CP, Kang MH (2014) Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma. Br J Pharmacol 171:5330–5344CrossRefPubMedPubMedCentral

27.

Tagde A, Singh H, Kang MH, Reynolds CP (2014) The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. Blood Cancer J 4:e229CrossRefPubMedPubMedCentral

28.

Rice P, Longden I, Bleasby A.EMBOSS (2000) The European molecular biology open software suite. Trends Genet 16:276–277CrossRefPubMed

29.

Goujon M, McWilliam H, Li W, Valentin F, Squizzato S, Paern J, Lopez R (2010) A new bioinformatics analysis tools framework at EMBL-EBI. Nucleic Acids Res 38:695–699CrossRef

30.

McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R (2013) Analysis tool web services from the EMBL-EBI. Nucleic Acids Res 41:597–600CrossRef

31.

Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J, Thompson JD, Higgins DG (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega. Mol Syst Biol 7:539CrossRefPubMedPubMedCentral

32.

Marchler-Bauer A, Zheng C, Chitsaz F, Derbyshire MK, Geer LY, Geer RC et al (2013) CDD: conserved domains and protein three-dimensional structure. Nucleic Acids Res 41:348–352CrossRef

33.

Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T et al (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:252–258CrossRef

34.

Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201CrossRefPubMed

35.

Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. Proteomics protocols handbook. Humana Press, New York

36.

Esch D, Vahokoski J, Groves MR, Pogenberg V, Cojocaru V, Vom Bruch H et al (2013) A unique Oct4 interface is crucial for reprogramming to pluripotency. Nat Cell Biol 15:295–301CrossRefPubMed

Title: OCT4 spliced variants are highly expressed in brain cancer tissues and inhibition of OCT4B1 causes G2/M arrest in brain cancer cells
Authors: Malek Hossein Asadi
Khosrow Khalifeh
Seyed Javad Mowla
Publication date: 01-12-2016
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2016
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-016-2255-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

OCT4 spliced variants are highly expressed in brain cancer tissues and inhibition of OCT4B1 causes G2/M arrest in brain cancer cells

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2016

Long-term follow-up of a papillary tumor of the pineal region: addendum to a case report

Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma

Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study

Expression level of miRNAs on chromosome 14q32.31 region correlates with tumor aggressiveness and survival of glioblastoma patients

Time-delayed contrast-enhanced MRI improves detection of brain metastases: a prospective validation of diagnostic yield

Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma