Phosphorylated Insulin Like Growth Factor-â…  Receptor Regulating Sox2Expression Promotes Acquisition Of Stem Cell-Like Properties And Predicts The Prognostic Of The Patients With Gastric Cancer

Objectives:Phosphorylated insulin-like growth factor-1receptor (P-IGF-1R) displays a key role in tumor transformation and metastasis. It also plays critical roles in the survival, maintenance, and function of cancer stem cells. The aim of this study was to investigate the correlation between P-IGF-1R and stemness factor protein Sox2and the clinical significance of their expression in gastric carcinoma (GC).Methods:P-IGF-1R and Sox2expressed in227specimens were detected by immunohistochemistry. The correlation between P-IGF-IR and Sox2expression was determined. In addition, the association of their expression with clinicopathological features and survival data of GC was also analyzed.Results:P-IGF-1R (41.9%), IGF-1R(45.8%) and Sox2(22.5%) were frequently expressed in GC.P-IGF-1R was associated with TNM stages, lymph node metastasis, operation performed (P<0.05).Sox2was associated with operation performed, lymph node metastasis, distant metastasis and TNM stages (P<0.05).Furthermore,P-IGF-1R overexpression positively correlated with Sox2over-expression(r=0.301, P<0.001). Univariate and multivariate analysis showed that P-IGF-1R and Sox2co-overexpression were correlated with poor prognosis of GC compared with low expression of both P-IGF-1R and Sox2(P<0.01), including TNM stage, operation method and adjuvant chemotherapy.Furthermore,95patients receiving adjuvant FOLFOX-4or XELOX chemotherapy who co-expressed IGF-1R/Sox2had a poor prognosis (P<0.05).Conclusions:The factors of TNM stage, operation method and adjuvant chemotherapy affect the prognosis of patients with GC. The positive expression of P-IGF-1R and Sox2in GC may indicate poor overall survival, emerging as new independent prognostic biomarkers and predict the potential therapeutic effect of target therapy for GC as well. Objectives:The benefit of neoadjuvant chemotherapy (NAC) in the management of gastroesophageal and gastric cancer still remains controversial. The aim of this meta-analysis of the published studies is to evaluate the role of the neoadjuvant chemotherapy with the regimen on the basis of the Flurouracil-based for gastroesophageal and gastric cancer.Methods:Medline and manual searches were performed to identify all published randomized controlled trials (RCTs) investigating the efficacy of the neoadjuvant chemotherapy (NAC) with the Flurouracil-based regimen for the gastroesophageal and gastric cancer. All published controlled trials of neoadjuvant chemotherapyfor advanced gastroesophageal and gastric cancer vs. no therapy before surgeries were searched. Studies that included patients with metastases at enrollment were excluded. Primary endpoint was the odds ratio (OR) for improving overall survival rate of patients with gastroesophageal and gastric cancer. Secondary endpoints were the OR of efficiency for down-staging tumor and increasing Ro resection in patients with gastroesophageal and gastric cancer. Safety analyses were also performed. The odds ratio was the principle measurement of effect, which was calculated as the treatment group (neoadjuvant chemotherapy plus surgery treatment) versus the control group (surgery alone) and was presented as a point estimate with95%confidence intervals (CI). All calculations and statistical tests were performed using RevMan5.1software.Results:Seven RCTs were adopted for analysis. The meta-analysis showed that the neoadjuvent chemotherapy improve the overall survival rate (44.7%vs36.7%),[OR=1.40,95%confidence interval (CI):1.11-1.76;P=0.005], which was statistically significant. The3-year PFS rate was significantly higher for treatment group than for control group (37.7% vs27.3%),[OR=1.62,95%confidence interval (CI):1.21-2.15; p=0.001]. The rate of tumor down-stage was higher for treatment group than for control group (55.76%vs41.38%),[OR=1.77,95%confidence interval (CI):1.27-2.49; p=0.0009] and the Ro resection rate of the gastroesophageal and gastric cancer was higher for treatment group than for control group (75.11%vs68.56%),[OR=1.38,95%confidence interval (CI):1.03-1.85; P=0.03].which were statistically significant, respectively.No obvious safety concerns about mortality and complication s were raised in these trials. The perioperative mortality with no statistically significant difference between the two groups (5.08%vs4.86%)[OR=1.05,95%confidence interval (CI):0.57-1.94; P=0.87fixed-effect mode] and the complication rate was no statistically significant difference between the two groups (13.25%vs9.66%)[OR=1.40,95%confidence interval (CI):0.91-2.14; P=0.12fixed-effect mode].Trials from Western countries showed patients favoring NAC than those from Asian countries (OR=1.40,95%CI:1.07-1.83). Monotherapy regimens were inferior to multiple chemotherapy regimens (OR=1.40,95%CI:1.07-1.83). â…£ method of NAC was better than oral method (OR=1.41,95%CI:1.09-1.81).Conclusions:NAC with the Flurouracil-based regimen can safely improve overall survival rate of patients with gastroesophageal/gastric cancer. Additionally, NAC can down tumor stage and improve Ro resection. Objective:Members of the IGFR family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including gastric carcinoma (GC). The IGFR family, including IGF-1R, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of phosphorylated IGF-1R (P-IGF-1R) as a regulator of "sternness" in GC cells. In addition, we intend to investigate whether P-IGF-1R can promote the self-renewal of GC cells via stimulating the activity of the transcriptional factor Sox2and its underlying mechanisms. Similarly, we decide to investigate the role the specific IGF-1R inhibitor NVP-AEW541in the ability of self-renewal and migration and Sox2expression in the gastric cancer lines.Methods:Sphere formation assay was used to detect the self-renewal ability about the functional study of the stem-like cells. The Expression of P-IGF-1R and Sox2were analysed in GC cell lines. Transwell assay was performed to evaluate the migration ability of gastric stem-like cell. Western blotting was used to access whether the degradation the Sox2protein via ubiquitin-proteasome pathway assay. Western blotting and laser scanning confocal microscopy was used to determine the Sox2protein expression. Real-time RT-PCR was used to assess the expression of Sox2at mRNA level.Results:phosphorylation of IGF-1R by the addition of IGF-1ligand in two established GC cell lines (MKN-45and HGC-27) resulted in the induction of Sox2both in gene and protein level. Meanwhile, phosphorylation of IGF-1R also resulted in the increased atmosphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with a specific IGF-1R kinase inhibitor, NVP-AEW541, resulted in decreased expression of the Sox2both in gene and in protein level, and in loss of tumorsphere-forming ability. Additionally, we found that these cancer stem-like cells, when treated with NVP-AEW541, possessed a lower capacity to invade in vitro. More attractively, we found that the decrease of the Sox2protein expression due to the inactivated P-IGF-1R instead of the degradation of the protein via the proteasome pathway.Conclusion:These results indicate that phosphorylated IGF-1R plays critical roles in the survival, maintenance, and function of cancer stem cells instead of inhibiting the unbiquitnation-proteasomal degradation of Sox2, and enhancing its stability and expression. Additionally, these findings suggest that inhibiting IGF-1R may be an effective therapeutic strategy for gastric cancers that co-express IGF-1R and Sox2at high levels. Drugs that target IGF-1R might be an effective treatment for gastric cancer.