Expression and prognostic significance of cyclin‑dependent kinase inhibitor 1A in patients with resected gastric adenocarcinoma

Lin,Youdong; Wang,Xiaoting; Yu,Yinghao; Liu,Wei; Xie,Feilai; Ouyang,Xuenong; Huang,Qiaojia

doi:10.3892/ol.2017.7107

Expression and prognostic significance of cyclin‑dependent kinase inhibitor 1A in patients with resected gastric adenocarcinoma

Authors:
- Youdong Lin
- Xiaoting Wang
- Yinghao Yu
- Wei Liu
- Feilai Xie
- Xuenong Ouyang
- Qiaojia Huang
View Affiliations

Affiliations: Department of Experimental Medicine, Fuzhou General Hospital, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China, Department of Pathology, Fuzhou General Hospital, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China, Department of Oncology, Fuzhou General Hospital, Fuzong Clinical College of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
Published online on: September 29, 2017 https://doi.org/10.3892/ol.2017.7107
Pages: 7473-7482

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cyclin‑dependent kinase inhibitor 1A (CDKN1A) is an important cell cycleregulator, and has been identified to exhibit aberrant expression in various types of cancer tissues. However, the association between CDKN1A expression level and prognosis in patients with resected gastric adenocarcinoma (RGA) requires additional elucidation. In the present study, the CDKN1A expression profile in RGA tissues obtained from 217 patients were analyzed using immunohistochemistry. Its prognostic significance was evaluated by using the χ2 test, Kaplan‑Meier curves and the log‑rank test, and a multivariate Cox model analysis, during a median follow‑up time of 51 months. The results demonstrated that CDKN1A expression was significantly correlated with lymph node metastasis (LNM; P=0.001), recurrence (P<0.001) and overall survival (OS; P<0.001). In addition, the recurrence‑free survival (RFS) and OS times were significantly shorter in patients with low CDKN1A expression compared with those with high CDKN1A expression (RFS, 20 months vs. 69 months, P<0.001; and OS, 32 months vs. 70 months, P<0.001, respectively). Multivariate analysis additionally confirmed that low CDKN1A expression was significantly correlated with an increased risk of LNM (P=0.001), recurrence (P<0.001) and mortality (P<0.001). Therefore, these data suggest that low expression of CDKN1A has independent prognostic significance indicative of tumor progression and poor survival in patients with RGA. Evaluation of CDKN1A expression may assist in determining prognosis in patients with RGA.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006. View Article : Google Scholar : PubMed/NCBI
3	Liu C, Lu P, Lu Y, Xu H, Wang S and Chen J: Clinical implications of metastatic lymph node ratio in gastric cancer. BMC Cancer. 7:2002007. View Article : Google Scholar : PubMed/NCBI
4	Ohta K, Hoshino H, Wang J, Ono S, Iida Y, Hata K, Huang SK, Colquhoun S and Hoon DS: MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A. Oncotarget. 6:3211–3324. 2015. View Article : Google Scholar : PubMed/NCBI
5	Cazzalini O, Scovassi AI, Savio M, Stivala LA and Prosperi E: Multiple roles of the cell cycle inhibitor p21 (CDKN1A) in the DNA damage response. Mutat Res. 704:12–20. 2010. View Article : Google Scholar : PubMed/NCBI
6	Prives C and Gottifredi V: The p21 and PCNA partnership: A new twist for an old plot. Cell Cycle. 7:3840–3846. 2008. View Article : Google Scholar : PubMed/NCBI
7	Andries V, Vandepoele K, Staes K, Berx G, Bogaert P, Van Isterdael G, Ginneberge D, Parthoens E, Vandenbussche J, Gevaert K, et al: NBPF1, a tumor suppressor candidate in neuroblastoma, exerts growth inhibitory effects by inducing a G1 cell cycle arrest. BMC Cancer. 15:3912015. View Article : Google Scholar : PubMed/NCBI
8	Park C, Jeong NY, Kim GY, Han MH, Chung IM, Kim WJ, Yoo YH and Choi YH: Momilactone B induces apoptosis and G1 arrest of the cell cycle in human monocytic leukemia U937 cells through downregulation of pRB phosphorylation and induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. Oncol Rep. 31:1653–1660. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wei CY, Tan QX, Zhu X, Qin QH, Zhu FB, Mo QG and Yang WP: Expression of CDKN1A/p21 and TGFBR2 in breast cancer and their prognostic significance. Int J Clin Exp Pathol. 8:14619–14629. 2015.PubMed/NCBI
10	Li S, Wang C, Yu X, Wu H, Hu J, Wang S and Ye Z: miR-3619-5p inhibits prostate cancer cell growth by activating CDKN1A expression. Oncol Rep. 37:241–248. 2017. View Article : Google Scholar : PubMed/NCBI
11	Tang H, Wu Y, Liu M, Qin Y, Wang H, Wang L, Li S, Zhu H, He Z, Luo J, et al: SEMA3B improves the survival of patients with esophageal squamous cell carcinoma by upregulating p53 and p21. Oncol Rep. 36:900–908. 2016. View Article : Google Scholar : PubMed/NCBI
12	Wang X, Lin Y, Lan F, Yu Y, Ouyang X, Wang X, Huang Q, Wang L, Tan J and Zheng F: A GG allele of 3′-side AKT1 SNP is associated with decreased AKT1 activation and better prognosis of gastric cancer. J Cancer Res Clin Oncol. 140:1399–1411. 2014. View Article : Google Scholar : PubMed/NCBI
13	Yoo CH, Noh SH, Kim YI and Min JS: Comparison of prognostic significance of nodal staging between old (4th edition) and new (5th edition) UICC TNM classification for gastric carcinoma. International union against cancer. World J Surg. 23:492–497. 1999. View Article : Google Scholar : PubMed/NCBI
14	Ward JH: NCCN Guidelines and the International community. J Natl Compr Canc Netw. 9:133–134. 2011. View Article : Google Scholar : PubMed/NCBI
15	Wang X, Lin Y, Lan F, Yu Y, Ouyang X, Liu W, Xie F, Wang X and Huang Q: BAX and CDKN1A polymorphisms correlated with clinical outcomes of gastric cancer patients treated with postoperative chemotherapy. Med Oncol. 31:2492014. View Article : Google Scholar : PubMed/NCBI
16	Kawata N, Tsuchiya N, Horikawa Y, Inoue T, Tsuruta H, Maita S, Satoh S, Mitobe Y, Narita S and Habuchi T: Two surviving polymorphisms are cooperatively associated with bladder cancer susceptibility. Int J Cancer. 129:1872–1880. 2011. View Article : Google Scholar : PubMed/NCBI
17	Huang Q, Huang Q, Chen W, Wang L, Lin W, Lin J and Lin X: Identification of transgelin as a potential novel biomarker for gastric adenocarcinoma based on proteomics technology. J Cancer Res Clin Oncol. 134:1219–1227. 2008. View Article : Google Scholar : PubMed/NCBI
18	Galeano F, Rossetti C, Tomaselli S, Cifaldi L, Lezzerini M, Pezzullo M, Boldrini R, Massimi L, Di Rocco CM, Locatelli F, et al: ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene. 32:998–1009. 2013. View Article : Google Scholar : PubMed/NCBI
19	Morton JP, Jamieson NB, Karim SA, Athineos D, Ridgway RA, Nixon C, McKay CJ, Carter R, Brunton VG, Frame MC, et al: LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology. 139:586–597. 2010. View Article : Google Scholar : PubMed/NCBI
20	Brown SG, Knowell AE, Hunt A, Patel D, Bhosle S and Chaudhary J: Interferon inducible antiviral MxA is inversely associated with prostate cancer and regulates cell cycle, invasion and Docetaxel induced apoptosis. Prostate. 75:266–279. 2015. View Article : Google Scholar : PubMed/NCBI
21	Koh DI, Han D, Ryu H, Choi WI, Jeon BN, Kim MK, Kim Y, Kim JY, Parry L, Clarke AR, et al: KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Proc Natl Acad Sci USA. 111:pp. 15078–15083. 2014, View Article : Google Scholar : PubMed/NCBI
22	Sun Y, Yang S, Sun N and Chen J: Differential expression of STAT1 and p21 proteins predicts pancreatic cancer progression and prognosis. Pancreas. 43:619–623. 2014. View Article : Google Scholar : PubMed/NCBI
23	Belt EJ, Brosens RP, Delis-van Diemen PM, Bril H, Tijssen M, van Essen DF, Heymans MW, Beliën JA, Stockmann HB, Meijer S, et al: Cell cycle proteins predict recurrence in stage II and III colon cancer. Ann Surg Oncol. 19 Suppl 3:S682–S692. 2012. View Article : Google Scholar : PubMed/NCBI
24	Mitomi H, Ohkura Y, Fukui N, Kanazawa H, Kishimoto I, Nakamura T, Yokoyama K, Sada M, Kobayashi K, Tanabe S, et al: P21WAF1/CIP1 expression in colorectal carcinomas is related to Kras mutations and prognosis. Eur J Gastroenterol Hepatol. 19:883–889. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wu DW, Liu WS, Wang J, Chen CY, Cheng YW and Lee H: Reduced p21 (WAF1/CIP1) via alteration of p53-DDX3 pathway is associated with poor relapse-free survival in early-stage human papillomavirus-associated lung cancer. Clin Cancer Res. 17:1895–1905. 2011. View Article : Google Scholar : PubMed/NCBI
26	Young TW, Rosen DG, Mei FC, Li N, Liu J, Wang XF and Cheng X: Up-regulation of tumor susceptibility gene 101 conveys poor prognosis through suppression of p21 expression in ovarian cancer. Clin Cancer Res. 13:3848–3854. 2007. View Article : Google Scholar : PubMed/NCBI
27	Buchynska LG, Nesina IP, Yurchenko NP, Bilyk OO, Grinkevych VN and Svintitsky VS: Expression of p53, p21WAF1/CIP1, p16INK4A and Ki-67 proteins in serous ovarian tumors. Exp Oncol. 29:49–53. 2007.PubMed/NCBI
28	Khalili M, Vasei M, Khalili D, Alimoghaddam K, Sadeghizadeh M and Mowla SJ: Downregulation of the genes involved in reprogramming (SOX2, c-MYC, miR-302, miR-145, and P21) in gastric adenocarcinoma. J Gastrointest Cancer. 46:251–258. 2015. View Article : Google Scholar : PubMed/NCBI
29	Dai M, Al-Odaini AA, Arakelian A, Rabbani SA, Ali S and Lebrun JJ: A novel function for p21Cip1 and acetyltransferase p/CAF as critical transcriptional regulators of TGF β-mediated breast cancer cell migration and invasion. Breast Cancer Res. 14:R1272012. View Article : Google Scholar : PubMed/NCBI
30	Zhang H, Zhang X, Ji S, Hao C, Mu Y, Sun J and Hao J: Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1. Carcinogenesis. 35:1863–1871. 2014. View Article : Google Scholar : PubMed/NCBI
31	Liu J, Hu Y, Hu W, Xie X, Bella Ela A, Fu J and Rao D: Expression and prognostic relevance of p21WAF1 in stage III esophageal squamous cell carcinoma. Dis Esophagus. 25:67–71. 2012. View Article : Google Scholar : PubMed/NCBI
32	Watanabe M, Nakahata S, Hamasaki M, Saito Y, Kawano Y, Hidaka T, Yamashita K, Umeki K, Taki T, Taniwaki M, et al: Downregulation of CDKN1A in adult T-cell leukemia/lymphoma despite overexpression of CDKN1A in human T-lymphotropic virus 1-infected cell lines. J Virol. 84:6966–6977. 2010. View Article : Google Scholar : PubMed/NCBI
33	Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R, Liu YW, Liu XH, Zhang EB, Lu KH, et al: Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther. 14:268–277. 2015. View Article : Google Scholar : PubMed/NCBI