Expression and prognostic significance of cyclin‑dependent kinase inhibitor 1A in patients with resected gastric adenocarcinoma
- Authors:
- Published online on: September 29, 2017 https://doi.org/10.3892/ol.2017.7107
- Pages: 7473-7482
Abstract
Introduction
Gastric cancer is the most common digestive tract malignancy that affects ~1 million people per year worldwide (1), and >90% of these cases are gastric adenocarcinoma (GA). At present, surgery remains the primary method for treating patients with GA. Lymph node metastasis (LNM) usually indicates a poor prognosis of resected GA (RGA), as it is closely associated with widespread metastasis that will affect the survival of the patients (2,3). A reduced risk of metastasis and recurrence and improved survival time are the primary goals of cancer therapy. Therefore, it would be useful to identify a biomarker associated with LNM that may assist in predicting prognosis.
Cyclin-dependent kinase inhibitor 1A (CDKN1A; also known as p21), a cell cycle regulator which is encoded by the CDKN1A gene at chromosome 6p21.2, is primarily involved in mediating cell growth, proliferation, differentiation, DNA repair and apoptosis (4–6). Data from a number of studies have demonstrated that it assists in regulating tumor development by inducing cell cycle arrest, leading to a reduction in cancer cell growth rate (7,8). Aberrant expression of CDKN1A has been frequently observed in different types of cancer tissues (9–11). In the present study, in order to understand the association between CDKN1A expression and prognosis in patients with RGA, the correlation between the expression of CDKN1A and clinicopathological factors, LNM, recurrence rate, and survival in patients with RGA was evaluated by various statistical analyses.
Materials and methods
Patients
GA tissue samples for immunohistochemistry (IHC) were retrospectively collected from 217 patients who were diagnosed pathologically with primary GA and then underwent surgical resection between January 2003 and November 2008. Information was obtained from the medical records of each patient and follow-up records subsequent to treatment were monitored until March 2013. Survival data were obtained via telephone contact and the Social Security Death Index. Recurrence was diagnosed according to the criteria described in our previous study (12). Fluoropyrimidine-based regimens (fluoropyrimidine or fluoropyrimidine plus platinum) were used as first-line chemotherapy to treat all of the patients following resection of GA. The standards described in the guidelines of the International Union Against Cancer (UICC; 5th Edition) and the National Comprehensive Cancer Network's (NCCN) Clinical Practice Guidelines in Oncology (v.1.2011) (13,14) were used to determine the tumor-node-metastasis (TNM) stage and histological grade for each of the tissue samples used in the present study.
For comparison of the results of western blotting and IHC, GA tissue samples from 52 cases were collected from patients with primary GA who underwent surgical resection between March 2014 and December 2015.
The study was approved by the Ethics Committee of Fuzhou General Hospital (Fuzhou, China) and all patients provided informed consent.
IHC
IHC was used to determine the levels of CDKN1A in paraffin-embedded RGA (217 cases) and normal gastric tissues (30 cases). The anti-CDKN1A antibody was obtained from ZSGB-BIO (cat. no. TA808128; dilution, 1:150; Beijing, China). IHC was performed as described previously (12,15). The expression intensity of CDKN1A was scored from 0 to 3 according to the standards established by Kawata et al (16). Samples with a staining intensity of 0 or 1 were considered as low expression, and with staining intensity of 2 or 3 as high expression.
Hematoxylin and eosin (H&E) staining
H&E staining of paraffin-embedded normal gastric tissues and cancer tissues in patients with RGA were performed by a pathologist using an established methodology. The steps of H&E staining are briefly described as follows: i) Sections of tissue samples were dewaxed with xylene and washed with various concentrations of ethanol (100, 100, 95 and 80%); ii) stained with 0.5% hematoxylin for 5 min, washed with water for 10 min and then distilled water for 5 sec; iii) soaked in hydrochloric acid ethanol for 30 sec and then water for 15 min; iv) 0.5% eosinstaining for 2 min; v) conventional dehydration, transparency and neutral resins mount; vi) the results were observed using light microscopy (magnification, ×200). All steps were performed at room temperature (25°C).
Western blotting
As described previously (17), total protein from cancer tissues was extracted using RIPA lysis buffer (cat. no. P0013B) and quantified using the BCA Protein Assay kit (cat. no. P0012S), and western blotting was performed using a SDS-PAGE Gel preparation reagent kit [cat. no. P0012A: P0012A-1, 30% Acr-Bis (29:1); P0012A-2, 1M Tris-HCl, pH 8.8; P0012A-3, 10% SDS; P0012A-4, ammonium persulfate; P0012A-5, TEMED; P0012A-6, 1M Tris-HCl, pH 6.8; SDS-PAGE Sample Loading Buffer (5X), cat. no. P0015], blocking buffer (cat. no. P0023B) and enhanced chemiluminescence reagents (ECL; cat. no. P0018) (all of the above reagents were from Beyotime Institute of Biotechnology, Haimen, China). Briefly, the proteins (30 µg per lane) were subjected to SDS-PAGE gel electrophoresis (concentrated gel, 5%; separation gel, 12%) and then transferred to polyvinylidene membranes. Following incubation with blocking buffer at room temperature for 30 min, the membranes were incubated with primary polyclonal rabbit anti-human CDKN1A antibody (cat. no. SC-397; dilution, 1:300; ZSGB-BIO) or primary polyclonal rabbit anti-human GAPDH antibody (cat. no. 2118S; dilution, 1:1,000; Cell Signaling Technology, Inc., Danvers, MA, USA) overnight at 4°C. Following three washes with TBST the membranes were incubated with secondary goat anti-rabbit antibody IgG-horseradish peroxidase (cat. no. M21002M; dilution, 1:2,000; abMart Company, Shanghai, China) for 4 h at room temperature. Finally, the bands were visualized using ECL and analyzed with a chemiluminescence imager system (Image Quant LAS4000 mini system; GE Healthcare, Chicago, IL, USA).
Statistical analysis
SPSS 17.0 statistical software (SPSS, Inc., Chicago, IL, USA) was used to conduct data analysis, including the correlation between CDKN1A expression and the clinicopathological characteristics and prognosis of patients. The methods used in this analysis were the χ2 test, and Kaplan-Meier and log-rank analyses of recurrence-free survival (RFS) and overall survival (OS) times in months. Additionally, univariate and multivariate Cox models were used to assess the prognostic ability of known unfavorable pathological factors, and the correlation between CDKN1A expression profiles and recurrence or survival. The agreement between CDKN1A expression detected by western blot and immunohistochemical analyses was evaluated by Spearman's rank correlation analysis. All tests were two-sided, and P<0.05 was considered to indicate a statistically significant difference.
Results
Clinicopathological characteristics of patients
The clinicopathological characteristics of the 217 RGA patients are summarized in Table I. All patients had received fluoropyrimidine or fluoropyrimidine plus platinum agents as first-line chemotherapy for an average of 4 cycles following resection. The patients comprised 153 males and 64 females; 135 patients were <60 years old, and 82 patients were ≥60 years old, the median age was 60 years. At the time of resection, 147 patients (67.7%) presented with LNM. In 145 cases (66.8%), the tumors were moderately or well-differentiated, while the remaining 72 cases (33.2%) exhibited poorly differentiated histology. By the end of follow-up, 126 had developed recurrent disease, and 116 patients had succumbed to the disease. The median times to recurrence and mortality were 41 and 54 months, respectively. The median time of observation was 51 months.
CDKN1A expression and correlation between CDKN1A expression and clinicopathological characteristics
CDKN1A exhibited differential expression patterns in RGA and normal gastric tissues. In normal gastric tissues, CDKN1A protein was located mainly in the cell nuclei, whereas CDKN1A protein exhibited nuclear and cytoplasmic expression in RGA tissues. Representative IHC results of the different intensities of CDKN1A expression in RGA tissues and in normal gastric tissues are presented in Fig. 1, along with their corresponding H&E staining results. Representative western blot results are shown in Fig. 2. Resected tumor tissues from 118 cases (54.4%) of RGA exhibited high CDKN1A expression, whereas those from 99 patients (45.6%) demonstrated low CDKN1A expression (Table I). As summarized in Table II, CDKN1A expression was significantly associated with LNM (P=0.001), recurrence (P<0.001), and survival (P<0.001), as determined by χ2 test. No significant associations between CDKN1A expression and other clinicopathological characteristics, including age, gender, histological grade, gross pathology, tumor site, and postoperative chemotherapy, were observed (Table II).
 | Table II.Association between CDKN1A expression and characteristics of patients with resected gastric adenocarcinoma (n=217). |
Identification of prognostic factors associated with OS
The 5-year OS rate of the entire patient group was 46.5% (Table I). Data from the χ2 and log-rank tests indicated that patients with low CDKN1A expression exhibited a significantly poorer survival rate (25.3%; χ2 P<0.001) and lower median OS time (log-rank P<0.001; Tables II and III) compared with patients with high CDKN1A expression. As demonstrated in Table III, other factors identified by χ2 and log-rank tests to be associated with poor survival included LNM (P<0.001 and P<0.001, respectively), advanced T stage (P<0.001 and P<0.001, respectively), and postoperative chemotherapy with fluoropyrimidine only (P=0.008 and P=0.002, respectively). The results of the Kaplan-Meier analysis demonstrated that patients with low CDKN1A expression exhibited a significantly shorter OS time compared with those with high CDKN1A expression (median, 32 months vs. 70 months, P<0.001; Fig. 3A).
| Table III.Association between OS and characteristics of patients with resected gastric adenocarcinoma (n=217). |
Results from the univariate and multivariate Cox analyses additionally confirmed that positive LNM (P<0.001 and P=0.006, respectively), advanced T stage (T3/T4) (P<0.001 and P=0.001, respectively), postoperative chemotherapy with fluoropyrimidine only (P=0.003 and P=0.003, respectively) and low CDKN1A expression (P<0.001 and P<0.001, respectively) were significantly associated with increased risk of mortality (Table IV). Taken together, these data suggest that CDKN1A was a statistically significant independent prognostic significance for OS in patients with RGA.
Identification of prognostic factors associated with recurrence risk
The overall recurrence rate of the whole patient cohort was 58.1% (Table I). Data from the χ2 and log-rank tests indicated that patients with low CDKN1A expression exhibited a significantly higher recurrence rate (79.8%; χ2 P<0.001) and lower median recurrence-free survival (log-rank P<0.001) compared with those with high CDKN1A expression (Tables II and V). As demonstrated in Table V, other factors identified by χ2 and log-rank tests to be associated with a higher recurrence rate included LNM (P<0.001 and P<0.001, respectively), and T3/T4 stage (P<0.001 and P<0.001, respectively). The results of the Kaplan-Meier analysis indicated that patients with low CDKN1A expression exhibited a significantly shorter RFS time compared with those with high CDKN1A expression (median, 20 vs. 69 months, P<0.001; Fig. 3B).
| Table V.Association between recurrence and characteristics of patients with resected gastric carcinoma (n=217). |
Results from the univariate and multivariate Cox analyses demonstrated that LNM (P<0.001 and P=0.001, respectively), advanced T stage (P<0.001 and P=0.003, respectively), postoperative chemotherapy with fluoropyrimidine only (P=0.038 and P=0.007) and low CDKN1A expression (P<0.001 and P<0.001) were significantly associated with increased risk of recurrence (Table VI). Taken together, these data suggest that CDKN1A was a statistically significant independent prognostic significance for recurrence risk in patients with RGA.
Identification of risk factors associated with LNM
At the time of surgical resection, 79 of 99 patients (79.8%) with low CDKN1A expression presented with LNM, compared with 68 of 118 patients (57.6%) with high CDKN1A expression, a difference that was identified to be significant (P=0.001 by χ2 test; Tables II and VII). Univariate and multivariate logistic regression analyses additionally demonstrated that low CDKN1A expression was significantly associated with increased risk of LNM (P=0.001 and P=0.001, respectively). Other factors, including gross pathology (P=0.02 and P=0.035 from univariate and multivariate analyses, respectively) and advanced T stage (T3/T4; P=0.001 and P=0.005, from univariate and multivariate analyses, respectively) were also significantly associated with LNM (Table VII). Taken together, these data suggest that CDKN1A was a statistically significant independent risk factor for LNM in patients with RGA.
Correlation between western blot and IHC analyses for detection of CDKN1A
As presented in the representative results of Fig. 2, CDKN1A protein levels in tissues from 52 patients with RGA detected by western blotting and IHC exhibited a good correlation (r=0.872, P<0.001), which was obtained by scanning the western-blot bands with the gel analysis system to obtain the gray value, and then performing Spearman's rank correlation analysis to analyze the correlation between the gray values and their corresponding IHC scores so as to plot the scatter plot (Fig. 4). These data suggest that CDKN1A expression in RGA tissues may be determined by either western blotting or immunohistochemical analysis.
Discussion
The results of the present study demonstrated that low CDKN1A expression in GA tissues was associated with LNM and poor prognoses, as indicated by the shorter survival times and increased recurrence risks in these patients. Thus, CDKN1A appears to have independent prognostic significance in patients with RGA.
Previously published data have demonstrated that CDKN1A is a tumor suppressor due to its ability to induce cell cycle arrest (18–21). Confirming this role, downregulation of CDKN1A has been identified in different cancer tissues, and has been associated with poor prognoses in various types of human cancer, such as pancreatic and colon cancer, primary hepatocellular carcinoma, early-stage human papillomavirus-associated lung cancer and ovarian cancer (4,22–27). Khalili et al (28) revealed that low CDKN1A expression level may be associated with gastric cancer initiation and progression. However, there have been conflicting results in terms of the CDKN1A expression profiles in different cancer tissues. Certain studies have identified that CDKN1A overexpression in cancer tissues is associated with tumor aggressiveness and poor survival: Dai et al (29) suggested that CDKN1A expression in breast cancer tissues was correlated with LNM and poor survival of patients with breast cancer, and increased MDA-MB231 breast cancer cell migration and invasion via transforming growth factor β-mediated mothers against decapentaplegic homolog 3 acetylation. In addition to the aforementioned studies (4,22–27), there have been other investigations indicating that low expression of CDKN1A in various cancer tissues is associated with poor prognosis (30,31). The molecular mechanism by which different CDKN1A expression levels affect prognoses in patients with different types of cancer remains unclear and requires additional investigation. The present study identified that low expression of CDKN1A in RGA tissues was associated with poor prognosis in patients with gastric cancer.
As CDKN1A is a tumor suppressor, we hypothesize that epigenetic changes, such as promoter methylation, may be one of the mechanisms underlying the low CDKN1A expression in RGA tissues; promoter methylation is capable of inhibiting gene transcript and protein expression, as identified by Watanabe et al (32), who suggested that abnormal genomic methylation may be involved in the reduced expression of CDKN1A in adult T-cell leukemia/lymphoma (32). A study conducted by Nie et al (33) indicated that long noncoding RNAs (lncRNA) may also serve a role in regulation of CDKN1A transcription; the authors demonstrated that the lncRNA antisense noncoding RNA in the INK4 locus was upregulated in non-small cell lung cancer (NSCLC) tissues, and that this lncRNA promoted NSCLC cell proliferation and inhibited NSCLC cell apoptosis through the inhibition of Krüppel-like factor 2 and CDKN1A transcription (33). These studies additionally demonstrate that CDKN1A is a key regulator of the cell cycle, and may be a target for cancer treatment.
In conclusion, the present study indicated, via multiple statistical analyses, that low expression level of CDKN1A in RGA tissues was significantly associated with LNM, a shorter survival time and a high recurrence rate and risk of mortality. CDKN1A demonstrated important prognostic significance, and may be used as an independent prognostic factor for patients with RGA.
Acknowledgements
The present study was supported by grants from the National NaturalScience Foundation of China (grant no. 81372788), the Medical Scientific Research Key Foundation of Nanjing Command (grant no. 11Z032), and the Natural Science Foundation of Fujian Province Grant (grant no. 2014J01427), all awarded to Professor Qiaojia Huang; the Medical Scientific Innovation Foundation of Nanjing Command (grant no. 2013-MS122), awarded to Professor Yinghao Yu; and the National Natural Science Foundation of China (grant no. 81274002), awarded to Professor Xuenong Ouyang.
References
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
Ward JH: NCCN Guidelines and the International community. J Natl Compr Canc Netw. 9:133–134. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 |
