In this study, we first used immunohistochemical method to detect the expression of p53R2 protein in LSC tissues. We found that expression of p53R2 is mainly located in the cytoplasm, due to the location of p53R2 protein is affected by a various of factors, a study showed that redistribution of p53R2 protein occurs in response to signals that initiate DNA replication from the cytoplasm to the nucleus [
19]. Therefore, we speculated that the possible reason is that p53R2 protein did not exert its role translocating into the nucleus for DNA repair and DNA synthesis during the S phase when R2 subunit is available, in addition, p53R2, R2 binding to p53 located in the cytoplasm in quiescent cells, Which is consistent with prior studies [
20,
21]. Chi-square test analysis revealed that p53R2 protein expression and clinical stage has a significantly positive correlation, suggesting that p53R2 protein expression and the occurrence and development of LSC is closely related. Hsu NY studies have shown that p53R2 protein is closely related to the differentiation, stage and lymph node metastasis of NSCLCs and plays an important role in the early stages of recurrence [
22],Okumura’s study revealed that p53R2 protein expression was associated with lymph node metastasis, depth of invasion, and clinical stage of esophageal squamous cell carcinoma. [
15],The expression of p53R2 was also correlated with tumor size, local lymph node metastasis and histological classification [
23], Similarly, the study of Shigeto Matsushita revealed that the expression of p53R2 protein was associated with the depth of invasion and clinical stage of melanoma [
24]. All of these studies suggested that p53R2 protein is closely related to the development of tumors, which is agreement with our study.
The relationship between the expression of p53R2 protein and the prognosis of patients with LSC has not been reported. In this study, Kaplan-Meier survival analysis revealed that p53R2 protein expression, tumor size, clinical stage, T stage, N stage and M stage were the prognostic factors for LSC patients(
P<0.05). Overexpression of p53R2 protein group of patients with LSC, the average overall survival time of 34.7 months, is far lower than that with low expression of p53R2 with overalls survival time of 84.8 month. Cox multivariate analysis revealed that p53R2 protein expression, N stage and M stage could be used as an independent prognostic factor for assessing survival time of LSC patients, which is consistent with Hiroshi Okumura et al. in NSCLCs, esophageal squamous cell carcinoma, oral squamous cell carcinoma and melanoma, and the prognosis is poor in patients with overexpression of p53R2 protein. [
15,
22‐
24]. Souichi Yanamoto’s study showed that p53R2 promotes tongue cancer invasion through E-cadherin/β-catenin pathway [
25]. P53R2 is closely related to tumorigenesis, overexpression of p53R2 could cause myelodysplasia syndrome and acute myeloid leukemia [
26]. Recently, Xia Xu found that overexpression of p53R2 and RRM2 could selectively induce the occurrence of lung cancer in transgenic mice. [
27]. Abid et al. reported that activated ribonucleotide reductase could increase the production of deoxyribonucleotide triphosphate and induce cell division. The functional activation or overexpression of p53R2 as ribonucleotide reductase leads to the tumorigenicity or cell division via the p53 signaling pathway in tumors of p53 wild-type [
28]. Overexpression of the p53R2 protein affects the DNA repair regulated by the p53 gene, Increased base error insertion, increased risk of mutation, leading to genome instability and induce tumorigenesis [
29]. Genetic polymorphisms can affect gene expression, enzyme function, protein-to-environment interactions, and risk of susceptible to carcinoma [
30]. ZongLin Deng
,s reported newly identified polym-orphisms in the p53R2 gene,It was found that the 3 ‘end of the p53R2 gene had three gene polymorphisms and one gene polymorphism at the 5’ end, which could increase the risk of carcinoma [
31].Before the formation of cancer cells, p53R2 provides dNTPs for DNA repair and increases the expression of p21while decreasing the expression of cyclin D in wild-type p53 cell to arrest cell cycle in order to repair damaged DNA. After the formation of malignancy, their increasing demands for nutrients and support, p53R2 may contribute to cancer cell progression especially when p21 presents in cytoplasm [
32]. However, the mechanism of p53R2 protein development in LSC is unclear. Radiosensitivity of ESCC cell lines has been improved by the inhibition of siRNA for p53R2 [
33]. Tumor growth is suppressed and sensitivity of 5-FU is increased in oral cancer cells by p53R2 RNA-interference [
34]. Knocking down p53R2 of LNCaP cells could block DNA repair and also inhibited the induction of p21 [
35]. Exploring the molecular pathway mechanism will be a meaningful attempt. The above evidence showed that p53R2 expression plays a critical role in the occurrence and prognosis of tumors. P53R2 small molecule inhibitors may open a new chapter in the effective treatment of cancer for the clinical development and application of anti-cancer drugs.
In summary, overexpression of p53R2 is associated with poor prognosis in LSC. the expression of p53R2 protein can be used as an independent prognostic factor for assessing the overall survival time of patients with LSC, suggesting that p53R2 protein plays an important role in the development and progression of LSC and is expected to be a potential target for the treatment of LSC.