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Cyclin-Dependent Kinase Inhibitor 3 Promoted Cell Proliferation by Driving Cell Cycle from G1 to S Phase in Esophageal Squamous Cell Carcinoma.

ABSTRACT: Background and aims. Cyclin-dependent kinase inhibitor 3 (CDKN3) has been found playing a varying role in carcinogenesis, but its biological function in esophageal squamous cell carcinoma (ESCC) is unclear. The aim of this study was to demonstrate the role of CDKN3 in ESCC. Materials and Methods: Real-time PCR and Western blot was performed in 15 pairs of ESCC tissues and adjacent normal esophageal tissues. Then cell proliferation ability, cloning ability, cell cycle status and migration and invasion ability were explored in CDKN3 overexpressed TE1 cell line and CDKN3 siRNA transfected TE1 and KYSE70 cell lines. Finally, cell cycle related proteins CyclinD1, CDK4, pAKT, P53, P21, and P27 were tested by Western blot. Results: mRNA level was higher in 11 ESCC tissues compared to adjacent normal tissues, and an increased protein expression was further detected in 8 of those 11 ESCC tissues. Functional assays showed that CDKN3 overexpression promoted ESCC cell proliferation, colony formation, migration and invasion, and facilitated G1/S transition. Opposite results were also got after transfected with CDKN3 siRNA. Cell cycle associated protein pAKT, CyclinD1, CDK4 and P27 were upregulated and P53, P21 and were downregulated under CDKN3 overexpression. All the protein levels were found changed in the opposite direction when CDKN3 expression was disturbed by siRNA. Conclusions: Our study suggested that CDKN3 acted as an oncogene in human ESCC and may accelerate the G1/S transition by affecting CyclinD-CDK4 complex via regulating pAKT-p53-p21 axis and p27 independent of AKT.

SUBMITTER: Liu J

PROVIDER: S-EPMC6547974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe polymorphisms of the cyclin-dependent kinase inhibitor (CDKN1A) gene and matrix metalloproteinase-9 (MMP9) gene may increase one's susceptibility to malignancies. In this study, the association of the single nucleotide polymorphisms (SNPs) CDKN1A rs1059234 c.70C>T at the 3' untranslated region and MMP9 rs17576 (c.836A>G, p.Gln279Arg) with esophageal squamous cell carcinoma (ESCC) in Sudanese individuals were investigated.Materials and methodsA case-control study involving age- and gender-matched groups were conducted in a cancer center in eastern Sudan (Gadarif) between April and October 2020. The case group consisted of ESCC patients, whereas the control group comprised healthy subjects. Polymerase chain reaction-restriction fragment length polymorphism was performed for the genotyping of the CDKN1A rs1059234 and MMP9 rs17576 SNPs. The genotyping results were confirmed by Sanger sequencing.ResultsThe genotype distributions for CDKN1A rs1059234 and MMP9 rs17576 were in agreement with the Hardy-Weinberg equilibrium. The variant allele T in CDKN1 rs1059234 c.70C>T was significantly more prevalent in the ESCC patients than in the healthy controls [51.3% vs. 19.2%; OR = 4.4; 95% CI (2.6-7.4); p < 0.001]. Moreover, in CDKN1A rs1059234, the genotype TC + TT [76.9% vs. 38.4%; OR = 5.3; 95% CI (2.6-10.7); p < 0.001] was more frequent in the cases than in the controls, and it was significantly associated with ESCC risk. In MMP9 rs17576, the variant allele G was also significantly prevalent in the cases relative to the controls, and it was significantly associated with increased ESCC risk in the cases compared with the controls [27.5% vs. 1.9%; OR = 19.4; 95%CI (5.8-64.1); p < 0.001]. Both genotypes containing the allele G (AG + GG) were the most common genotypes in the cases [48.7% vs. 3.8%; OR = 23.7; 95%CI (6.8-81.7); p < 0.001], and they significantly increased the risk of ESCC.ConclusionA significant increase in ESCC risk is associated with the SNPs CDKN1A rs1059234 and MMP9 rs17576.

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Cyclin-Dependent Kinase Inhibitor 3 Promoted Cell Proliferation by Driving Cell Cycle from G1 to S Phase in Esophageal Squamous Cell Carcinoma.

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