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Current Gene Therapy

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ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

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Research Article

Poly(rC) Binding Protein 1 Represses the Translation of STAT3 through 5' UTR

Author(s): Ziwei Li, Xiaole Wang and Rong Jia*

Volume 22, Issue 5, 2022

Published on: 17 June, 2022

Page: [397 - 405] Pages: 9

DOI: 10.2174/1566523222666220511162934

Price: $65

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) is an oncogene and frequently overexpressed in cancers. However, the regulatory mechanisms of STAT3 expression are not fully understood. Poly(rC)-binding protein1 (PCBP1) is an RNA-binding protein that regulates mRNA stability, splicing, and translation. PCBP1 is a tumor suppressor and can inhibit the translation of several oncogenic genes.

Objective: We aimed to understand the regulatory mechanisms of STAT3 expression.

Methods: The 5' UTR or 3’ UTR regions of the human STAT3 gene were inserted upstream or downstream of the green fluorescent gene (GFP), respectively, which were used as reporter systems to analyze the inhibitory effects of PCBP1 on the STAT3 gene expression. The deletion and point mutation in 5' UTR were used to search the essential regulatory sequences of the translation inhibition. The mutations of PCBP1 protein were analyzed in the cBioPortal online service. The effects of mutated PCBP1 proteins on STAT3 expression, cancer cell proliferation, and colony formation were analyzed in oral squamous cell carcinoma (OSCC) cell lines.

Results: PCBP1 inhibits mRNA translation through a motif in the 5' UTR of STAT3. Moreover, we found two leucine residues (Leu100 and Leu102) of PCBP1 protein frequently mutated in cancers. These mutations abolished the inhibition function of PCBP1 on STAT3 translation. Surprisingly, in contrast to wild-type PCBP1 protein, these mutations can promote the growth and colony formation of cancer cells.

Conclusion: Overall, we demonstrate that PCBP1 can inhibit the expression of STAT3 through its 5' UTR, and two leucine residues of PCBP1 protein are essential for its functions.

Keywords: STAT3, UTR, PCBP1, translation inhibition, cancer, gene mutation.

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[1]
Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264(5164): 1415-21.
[http://dx.doi.org/10.1126/science.8197455] [PMID: 8197455]
[2]
Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol 2020; 80: 106210.
[http://dx.doi.org/10.1016/j.intimp.2020.106210] [PMID: 31972425]
[3]
Carpenter RL, Lo HW. STAT3 target genes relevant to human cancers. Cancers (Basel) 2014; 6(2): 897-925.
[http://dx.doi.org/10.3390/cancers6020897] [PMID: 24743777]
[4]
Choi HJ, Han JS. Overexpression of phospholipase D enhances Bcl-2 expression by activating STAT3 through independent activation of ERK and p38MAPK in HeLa cells. Biochim Biophys Acta 2012; 1823(6): 1082-91.
[http://dx.doi.org/10.1016/j.bbamcr.2012.03.015] [PMID: 22504301]
[5]
Leslie K, Lang C, Devgan G, et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 2006; 66(5): 2544-52.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-2203] [PMID: 16510571]
[6]
Itoh M, Murata T, Suzuki T, et al. Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 2006; 25(8): 1195-204.
[http://dx.doi.org/10.1038/sj.onc.1209149] [PMID: 16205632]
[7]
Hung W, Elliott B. Co-operative effect of c-Src tyrosine kinase and Stat3 in activation of hepatocyte growth factor expression in mammary carcinoma cells. J Biol Chem 2001; 276(15): 12395-403.
[http://dx.doi.org/10.1074/jbc.M010715200] [PMID: 11278729]
[8]
Yang J, Chatterjee-Kishore M, Staugaitis SM, et al. Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res 2005; 65(3): 939-47.
[PMID: 15705894]
[9]
Yang E, Lerner L, Besser D, Darnell JE Jr. Independent and cooperative activation of chromosomal c-fos promoter by STAT3. J Biol Chem 2003; 278(18): 15794-9.
[http://dx.doi.org/10.1074/jbc.M213073200] [PMID: 12600988]
[10]
Niu G, Briggs J, Deng J, et al. Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells. Mol Cancer Res 2008; 6(7): 1099-105.
[http://dx.doi.org/10.1158/1541-7786.MCR-07-2177] [PMID: 18644974]
[11]
Wu CJ, Sundararajan V, Sheu BC, Huang RY, Wei LH. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: Mechanism and therapeutic opportunity. Cancers (Basel) 2019; 12(1): E24.
[http://dx.doi.org/10.3390/cancers12010024] [PMID: 31861720]
[12]
Shukla S, Shishodia G, Mahata S, et al. Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: Implications in high-risk human papillomavirus infection. Mol Cancer 2010; 9: 282.
[http://dx.doi.org/10.1186/1476-4598-9-282] [PMID: 20977777]
[13]
Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer 2016; 138(11): 2570-8.
[http://dx.doi.org/10.1002/ijc.29923] [PMID: 26559373]
[14]
Xu YH, Lu S. A meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with non-small-cell lung cancer. Eur J Surg Oncol 2014; 40(3): 311-7.
[http://dx.doi.org/10.1016/j.ejso.2013.11.012] [PMID: 24332948]
[15]
Grandis JR, Drenning SD, Zeng Q, et al. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc Natl Acad Sci USA 2000; 97(8): 4227-32.
[http://dx.doi.org/10.1073/pnas.97.8.4227] [PMID: 10760290]
[16]
Ryu K, Choy E, Yang C, et al. Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J Orthop Res 2010; 28(7): 971-8.
[http://dx.doi.org/10.1002/jor.21088] [PMID: 20063378]
[17]
Ding BB, Yu JJ, Yu RY, et al. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. Blood 2008; 111(3): 1515-23.
[http://dx.doi.org/10.1182/blood-2007-04-087734] [PMID: 17951530]
[18]
Benekli M, Xia Z, Donohue KA, et al. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood 2002; 99(1): 252-7.
[http://dx.doi.org/10.1182/blood.V99.1.252] [PMID: 11756179]
[19]
Laudisi F, Cherubini F, Monteleone G, Stolfi C. STAT3 interactors as potential therapeutic targets for cancer treatment. Int J Mol Sci 2018; 19(6): E1787.
[http://dx.doi.org/10.3390/ijms19061787] [PMID: 29914167]
[20]
Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem 1993; 62: 289-321.
[http://dx.doi.org/10.1146/annurev.bi.62.070193.001445] [PMID: 8352591]
[21]
Makeyev AV, Liebhaber SA. Identification of two novel mammalian genes establishes a subfamily of KH-domain RNA-binding proteins. Genomics 2000; 67(3): 301-16.
[http://dx.doi.org/10.1006/geno.2000.6244] [PMID: 10936052]
[22]
Wang X, Guo J, Che X, Jia R. PCBP1 inhibits the expression of oncogenic STAT3 isoform by targeting alternative splicing of STAT3 exon 23. Int J Biol Sci 2019; 15(6): 1177-86.
[http://dx.doi.org/10.7150/ijbs.33103] [PMID: 31223278]
[23]
Makeyev AV, Liebhaber SA. The poly(C)-binding proteins: A multiplicity of functions and a search for mechanisms. RNA 2002; 8(3): 265-78.
[http://dx.doi.org/10.1017/S1355838202024627] [PMID: 12003487]
[24]
Zhang T, Huang XH, Dong L, et al. PCBP-1 regulates alternative splicing of the CD44 gene and inhibits invasion in human hepatoma cell line HepG2 cells. Mol Cancer 2010; 9: 72.
[http://dx.doi.org/10.1186/1476-4598-9-72] [PMID: 20361869]
[25]
Cho SJ, Jung YS, Chen X. Poly (C)-binding protein 1 regulates p63 expression through mRNA stability. PLoS One 2013; 8(8): e71724.
[http://dx.doi.org/10.1371/journal.pone.0071724] [PMID: 23940783]
[26]
Pickering BM, Mitchell SA, Evans JR, Willis AE. Polypyrimidine tract binding protein and poly r(C) binding protein 1 interact with the BAG-1 IRES and stimulate its activity in vitro and in vivo. Nucleic Acids Res 2003; 31(2): 639-46.
[http://dx.doi.org/10.1093/nar/gkg146] [PMID: 12527772]
[27]
Guo J, Jia R. Splicing factor poly(rC)-binding protein 1 is a novel and distinctive tumor suppressor. J Cell Physiol 2018; 234(1): 33-41.
[http://dx.doi.org/10.1002/jcp.26873] [PMID: 30132844]
[28]
Wang H, Vardy LA, Tan CP, et al. PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer Cell 2010; 18(1): 52-62.
[http://dx.doi.org/10.1016/j.ccr.2010.04.028] [PMID: 20609352]
[29]
Kim SJ, Ju JS, Kang MH, et al. RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC. Theranostics 2020; 10(18): 7974-92.
[http://dx.doi.org/10.7150/thno.45037] [PMID: 32724453]
[30]
Shen Z, Liu B, Wu B, et al. FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis. Commun Biol 2021; 4(1): 540.
[http://dx.doi.org/10.1038/s42003-021-02071-8] [PMID: 33972660]
[31]
Mubaid S, Ma JF, Omer A, et al. HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting. Proc Natl Acad Sci USA 2019; 116(35): 17261-70.
[http://dx.doi.org/10.1073/pnas.1905172116] [PMID: 31405989]
[32]
Brown AS, Mohanty BK, Howe PH. Identification and characterization of an hnRNP E1 translational silencing motif. Nucleic Acids Res 2016; 44(12): 5892-907.
[http://dx.doi.org/10.1093/nar/gkw241] [PMID: 27067543]
[33]
Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 2010; 12(3): 286-93.
[http://dx.doi.org/10.1038/ncb2029] [PMID: 20154680]
[34]
Wagener R, Aukema SM, Schlesner M, et al. The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma. Genes Chromosomes Cancer 2015; 54(9): 555-64.
[http://dx.doi.org/10.1002/gcc.22268] [PMID: 26173642]

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