Expression of p21Waf1/Cip1 predicts response and survival of esophageal cancer patients treated by chemoradiotherapy

Abstract

Chemoradiotherapy is a multimodal therapy routinely used as a primary treatment for advanced esophageal cancer. However, it is beneficial only to patients who respond. To identify pretreatment markers predicting response and survival, we examined the expression of cell cycle regulatory molecules, p53, p21(Waf1/Cip1) cyclin D1, and CDC25B, in biopsy specimens from 76 patients with stage III and stage IV squamous cell carcinoma. Overexpression of p53, p21, cyclin D1 and CDC25B was observed in 58%, 30%, 28%, and 32% of patients, respectively. The expression of p21 correlated significantly with response to chemoradiotherapy (P = 0.0001). Survival of patients with p21-expressing tumors was better than that of patients with p21-negative tumors (P = 0.013). Expression of other genes was not significantly correlated with treatment response and survival. In patients with p53-negative tumors, survival of those patients with p21-positive tumors was significantly higher than that of those with p21-negative tumors (P = 0.0452), but no significant difference was found in patients with p53-positive tumors. Multivariate analysis revealed that p21 expression was an independent variable among pretreatment parameters in predicting survival. These results suggest that p21 expression is potentially useful for predicting the response to chemoradiotherapy and survival of patients with advanced esophageal squamous cell cancer.

Overexpression of CDC25B and LAMC2 mRNA and Protein in Esophageal Squamous Cell Carcinomas and Premalignant Lesions in Subjects from a High-Risk Population in China

“…Using an overall score of z4 (equivalent to at least moderate intensity in more than one fourth of the cells), 59% of ESCC cases in our study were called positive. This 59% positivity is consistent with reports from previous ESCC studies [68% for Xue et al (35), 50% for Kishi et al (16), 48% for Nishioka et al (15), and 32% for Nakamura et al (34)]. …”

“…In the present study, we evaluated mRNA expression of these two genes in 73 new ESCC patients from the same high-risk area using a more quantitative method, real-time quantitative reverse transcription-PCR, and confirmed our previous results: CDC25B mRNA was overexpressed in nearly two thirds of cases and LAMC2 mRNA was overexpressed in 89%. Although CDC25B overexpression in ESCC has been previously reported (8,34), to our knowledge, our two studies represent the first reports of overexpression of LAMC2 mRNA in ESCC.…”

“…None of the metrics we evaluated for CDC25B protein expression showed a relation to survival. Four previous studies also reported on the relation of CDC25B protein expression to survival in ESCC cases (15,16,34,35), but none reported a significant association.…”

Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21WAF1/CIP1

“…59 Secondly, p21 has been characterized for a long time as an inhibitor of cell proliferation and the expression of p21 correlates significantly with response to chemotherapy. 60 [31][32][33] Taken together these data suggest that the long-term downregulation of Plk1 induces an accumulation of the kinase inhibitor p21, tumor suppressor p73, and pro-apoptotic protein Bax in HeLa cells, which render cells more sensitive to cisplatin and camptothecin. The increased level of p21 after the knockdown of Plk1 could be a general feedback regulation, since it can also be observed in non-transformed retina epithelial cells.…”

The Role of Glycogen Synthase Kinase 3-β in Immunity and Cell Cycle: Implications in Esophageal Cancer

“…The P21-positive group had a five-year survival rate of 50 % compared to the 13.4 % survival rate of the P21-negative group, which suggested that P21 is a good prognostic indicator for EC (Kuwahara et al 1999). Moreover, expression and polymorphisms of P21 are closely related with therapeutic outcomes (Bahl et al 2000;Nakamura et al 2004). Overexpression of GSK3b has been shown to directly downregulate P21 expression by phosphorylation at Thr57, leading to proteasome-mediated degradation, whereas inhibition of GSK3 with lithium chloride interfered with P21 degradation and increased P21 protein levels about ten-fold in EC (Rossig et al 2002).…”