PAX8 is transcribed aberrantly in cervical tumors and derived cell lines due to complex gene rearrangements

López–Urrutia, Eduardo; Pedroza-Torres, Abraham; Fernández‐Retana, Jorge; Leon, David Cantu De; Morales-González, Fermín; Jacobo-Herrera, Nadia; Peralta‐Zaragoza, Oscar; García-Méndez, Jorge; García-Castillo, Verónica; Bautista-Isidro, Osvaldo; Pérez‐Plasencia, Carlos

doi:10.3892/ijo.2016.3515

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…In the present study, MSK2 and PAX8 expression levels were positively correlated in tumor cells, which was expected since there is a correlation between PAX8 and CREB1 as well as ATF1, which triggers cell proliferation and transformation . Moreover, PAX8 regulates cell proliferation and is frequently abnormally activated in SCC . According to previous reports, PAX8 can regulate E2F1 and affect the phosphorylation of RB, to then regulate the sequential target genes related to tumor cell proliferation, survival, and migration .…”

Section: Discussionsupporting

confidence: 72%

“…14 Moreover, PAX8 regulates cell proliferation 32,33 and is frequently abnormally activated in SCC. 34,35 According to previous reports, PAX8 can regulate E2F1 and affect the phosphorylation of RB, to then regulate the sequential target genes related to tumor cell proliferation, survival, and migration. 36 When MSK2 was knocked down in tumor cells, cell proliferation, viability, tumor volume, and tumor weight were all reduced.…”

Section: Discussionmentioning

confidence: 99%

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MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB‐E2F1/cyclin A2 axis

Wang

et al. 2019

J of Cellular Biochemistry

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Patients with cervical cancer have abnormal cell proliferation and invasion after many years of latency. However, the precise mechanisms remain unclear.Mitogen-and stress-activated kinase 2 (MSK2) is a serine/threonine kinase which displays a phenotype that promotes tumor growth and metastasis in many different types of tumors. The aim of the present study was to determine the effects of MSK2 on the proliferation of cervical cancer cells and elucidate the signaling pathways through which MSK2 exerts its effects in the pathogenesis of squamous cell carcinoma (SCC). Our results confirmed that MSK2 expression was significantly upregulated in cervical cancer cells both in vivo and in vitro. We further found that the expression patterns of paired-box gene 8 (PAX8) and MSK2 were positively correlated in cervical cancer specimens. Moreover, MSK2 knockdown inhibited the phosphorylation of PAX8 and retinoblastoma protein (RB), and suppressed the sequential expressions of cell proliferation factors E2F1 and cyclin A2, resulting in the inhibition of SCC cell proliferation and tumor formation. Thus, this study demonstrates that MSK2 has oncogenic effects in the formation and development of SCC via the PAX8/RB-E2F1/cyclin A2 axis. K E Y W O R D Scell proliferation, cervical cancer, MSK2, PAX8, RB-E2F1/cyclin A2 axis

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB‐E2F1/cyclin A2 axis

Wang

et al. 2019

J of Cellular Biochemistry

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“…Previously, it has been reported that several novel PAX8 transcripts can be observed in cervical carcinoma, indicating differential regulation properties during carcinogenesis (44).…”

Section: Discussionmentioning

confidence: 99%

GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

Koel

Võsa

Lepamets

et al. 2021

Preprint

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Background The uterine cervix has an important role in female reproductive health, but not much is known about the genetic determinants of cervical biology and pathology. Genome-wide association studies (GWAS) with increasing sample sizes have reported a few genetic associations for cervical cancer. However, GWAS is only the first step in mapping the genetic susceptibility and thus, the underlying biology in cervical cancer and other cervical phenotypes is still not entirely understood. Here, we use data from large biobanks to characterise the genetics of cervical phenotypes (including cervical cancer) and leverage latest computational methods and gene expression data to refine the association signals for cervical cancer. Methods Using Estonian Biobank and FinnGen data, we characterise the genetic signals associated with cervical ectropion (10,162 cases/151,347 controls), cervicitis (19,285/185,708) and cervical dysplasia (14,694/150,563). We present the results from the largest trans-ethnic GWAS meta-analysis of cervical cancer, including up to 9,229 cases and 490,304 controls from Estonian Biobank, the FinnGen study, the UK Biobank and Biobank Japan. We combine GWAS results with gene expression data and chromatin regulatory annotations in HeLa cervical carcinoma cells to propose the most likely candidate genes and causal variants for every locus associated with cervical cancer. We further dissect the HLA association with cervical pathology using imputed data on alleles and amino acid polymorphisms. Results We report a single associated locus on 2q13 for both cervical ectropion (rs3748916, p=5.1 x 10-16) and cervicitis (rs1049137, p=3.9 x 10-10), and five signals for cervical dysplasia - 6p21.32 (rs1053726, p=9.1 x 10-9; rs36214159, 1.6 x 10-22), 2q24.1 (rs12611652, p=3.2 x 10-9) near DAPL1, 2q13 ns1049137, p=6.4 x 10-9) near PAX8, and 5p15.33 (rs6866294, p=2.1 x 10-9), downstream of CLPTM1L. We identify five loci associated with cervical cancer in the trans-ethnic meta-analysis: 1p36.12 (rs2268177, p= 3.1 x 10-8), 2q13 (rs4849177, p=9.4 x 10-15), 5p15.33 (rs27069, p=1.3 x 10-14), 17q12 (rs12603332, p=1.2 x 10-9), and 6p21.32 (rs35508382, p=1.0 x 10-39). Joint analysis of dysplasia and cancer datasets revealed an association on chromosome 19 (rs425787, p=3.5 x 10-8), near CD70. Conclusions Our results map PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1, HLA-B, and GSDMB as the most likely candidate genes for cervical cancer, which provides novel insight into cervical cancer pathogenesis and supports the role of genes involved in reproductive tract development, immune response and cellular proliferation/apoptosis. We further show that PAX8/PAX8-AS1 has a central role in cervical biology and pathology, as it was associated with all analysed phenotypes. The detailed characterisation of association signals, together with mapping of causal variants and genes offers valuable leads for further functional studies.

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“…miRs are thought to act as a negative regulator of a large number of genes through interaction with the 3′-untranslated regions (3’-UTR) of target mRNAs [ 6 ]. Pax8 is aberrantly expressed in several cancer types including papillary thyroid carcinoma [ 7 ], cervical tumors [ 8 ], and glioblastoma [ 9 ]. Overexpression of PAX8 has a poor prognostic impact on patients with endometrial cancer [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Paired box 8 suppresses tumor angiogenesis and metastasis in gastric cancer through repression of FOXM1 via induction of microRNA-612

Wang

Zheng

et al. 2018

J Exp Clin Cancer Res

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BackgroundPaired box 8 (PAX8) has been documented to be downregulated in gastric cancer. However, its biological function in this malignancy is poorly understood.MethodsIn the present work, we investigated the effects of PAX8 overexpression and knockdown on the aggressive phenotype of gastric cancer cells. We further checked the involvement of forkhead box M1 (FOXM1), a ubiquitously expressed oncogene that can facilitate gastric cancer progression, in the action of PAX8.ResultsEctopic expression of PAX8 blocked the migration and invasion of both AGS and SGC-7901 cells, but had no effect on cell proliferation. Conversely, knockdown of PAX8 enhanced gastric cancer cell migration and invasion. PAX8 overexpression inhibited epithelial-mesenchymal transition (EMT) and pro-angiogenic activity of gastric cancer cells. Mechanistically, PAX8 overexpression downregulated FOXM1 by stimulating microRNA (miR)-612 expression. Ectopic expression of miR-612 recapitulated the effect of PAX8 overexpression on gastric cancer cells, causing an inhibition of migration, invasion, EMT, and angiogenesis. Knockdown of miR-612 or overexpression of FOXM1 significantly reversed the tumor-suppressive activity of PAX8. In vivo studies further demonstrated that PAX8 overexpression restrained tumor angiogenesis and metastasis in nude mice, which was accompanied by increased expression of miR-612 and decreased expression of FOXM1.ConclusionsPAX8 exerts a tumor-suppressive effect against gastric cancer cells, largely through induction of miR-612 and repression of FOXM1. Therefore, restoration of PAX8 expression may offer therapeutic benefits in the treatment of gastric cancer.

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PAX8 is transcribed aberrantly in cervical tumors and derived cell lines due to complex gene rearrangements

Cited by 5 publications

References 39 publications

MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB‐E2F1/cyclin A2 axis

MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB‐E2F1/cyclin A2 axis

GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

Paired box 8 suppresses tumor angiogenesis and metastasis in gastric cancer through repression of FOXM1 via induction of microRNA-612

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