No abstract

The understanding of proliferative and apoptotic changes has aided the improvement of the diagnosis, treatment and prevention of gastric cancer. The present study aimed to investigate the clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 in gastric cancer. The expression levels of Ki-67, caspase-3 and p53 were evaluated on tissue microarrays of gastric carcinomas specimens by immunohistochemistry and compared with the clinicopathological parameters and survival time of the patients. It was observed that the elder or male patients with gastric cancer showed p53 overexpression compared with the younger or female patients, respectively (P<0.05). The expression of Ki-67 and p53 was positively associated with tumor-node-metastasis (TNM) staging (P<0.05). There was higher caspase-3 and p53 expression in the intestinal-type compared with the diffuse-type of carcinomas (P<0.05). There was a positive correlation among Ki-67, caspase-3 and p53 expression in gastric cancer (P<0.05). A Kaplan-Meier analysis indicated that there was positive correlation between caspase-3 expression and the adverse prognosis of the patients (P>0.05). Cox’s proportional hazards model indicated that the patient age, gender, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging, Lauren’s classification and caspase-3 expression were independent prognostic factors for gastric carcinomas (P<0.05). The data indicated that the expression of Ki-67, caspase-3 and p53 may be involved in the progression or differentiation of gastric carcinoma. This expression may be employed as an indicator of the pathobiological behavior and prognosis of gastric carcinomas.

No abstract

Dkk3 has been discovered during comparison of immortalized and parental cells. Its expression has been shown to reduce colony formation and induce apoptosis of cancer cells, acting as a tumor suppressor. Herein, we demonstrate that Dkk3 overexpression or protein treatment may inhibit colorectal cancer cell proliferation, migration, and invasion and that they may promote apoptosis and G2 phase arrest with hypoexpression of Bcl-2, cdc25B, cdc25c, N-cadherin, slug, and twist and hyperexpression of Bax and E-cadherin. This effect is consistent with that of recombinant Dkk3 exposure and blocked with anti-Dkk3 antibody. Dkk3 deletion in intestinal cells was not associated with the emergence of epithelial lesions; however, adenoma emerged after sodium desoxycholate treatment. At both mRNA and protein levels, Dkk3 expression was higher in normal than in cancer tissues (p&lt;0.05). Dkk3 mRNA expression was negatively associated with its promoter methylation, growth pattern, differentiation, and favorable prognosis in the patients with colorectal cancer (p&lt;0.05). Dkk3-related signal pathways in colorectal cancer included those of cellular adhesion and migration, melanogenesis, chemokine, Hedgehog, JAK-STAT, TOLL-like receptor, TGF-β, MAPK, and calcium signaling (p&lt;0.05). These findings indicate that Dkk3 expression levels can help assess cancer aggressiveness and patient prognosis. It might also suppress aggressive phenotypes and tumorigenesis as a molecular target in gene therapy.

Beclin 1 is encoded by Becn1, and plays a role in tumorigenesis, neurodegeneration, apoptosis and autophagy. Here, the aggressive phenotypes and relevant proteins were examined after Beclin 1 expression was altered in gastric cancer cells. We also observed the effects of Beclin 1 on gastric carcinogenesis using Becn1 knockout mice. Finally, clinicopathological significances of Beclin 1 expression were analyzed using meta- and bioinformatics analyses. Becn1 overexpression was found to inhibit proliferation, glucose metabolism, migration and invasion of gastric cancer cells, whereas its knockdown caused the opposite effects. Beclin 1 suppressed the tumor growth by decreasing proliferation and increasing apoptosis. The heterozygous abrogation of Becn1 in gastric pit, parietal and chief cells could not cause any epithelial lesion. Beclin 1-mediated chemoresistance was closely linked to the autophagy, Bax underexpression, and the overexpression of Bcl-2, LRP1, MDR1, and ING5. Bioinformatics analysis showed higher Becn1 mRNA expression in intestinal- than diffuse-type carcinomas (P&lt;0.05), and in male than female gastric cancer patients (P&lt;0.05). Becn1 hyperexpression was positively associated with both overall and progression-free survival rates of the cancer patients (P&lt;0.05). Meta-analysis showed that down-regulated Beclin 1 expression in gastric cancer was positively with lymph node metastasis, TNM staging, dedifferentiation and poor prognosis (P&lt;0.05). Becn1-related signal pathways in gastric cancer included prostate, lung, renal, colorectal, endometrial and thyroid cancers, glioma, and leukemia, the metabolism of amino acid, lipid and sugar, and some signal pathways of insulin, MAPK, TRL, VEGF, JAK-STAT, chemokine, p53, lysosome, peroxidome and ubiquitin-mediated protein degradation (P&lt;0.05). These suggested that Beclin 1 might be considered as a potential marker of gastric carcinogenesis, aggressiveness and prognostic prediction, and as a target of gene therapy in gastric cancer.

Paxillin encodes a focal adhesion-associated protein and is involved in the progression and aggressive phenotypes of malignancies through its interactions with the actin cytoskeleton and key signal transduction oncogenes. The present study aimed to investigate the clinicopathological and prognostic significance of paxillin in gastric cancer. The expression of paxillin was evaluated using tissue microarrays of gastric adjacent non-cancerous mucosa, adenoma and carcinoma specimens by immunohistochemistry. Paxillin expression was compared against clinicopathological parameters and the survival time of the patients. Paxillin was highly expressed in gastric adenoma compared with that in non-neoplastic mucosa and carcinoma (P<0.05). Paxillin expression was lower in the younger carcinoma patients compared with that in the elder carcinoma patients (P<0.05). Paxillin expression was negatively correlated with tumor size, depth of invasion and lymph node metastasis, but not with patient gender, lymphatic or venous invasion, or TNM staging (P>0.05). Higher paxillin expression was observed in intestinal-type compared with diffuse-type carcinoma (P<0.05). Kaplan-Meier analysis indicated a positive association between paxillin expression and cumulative survival rate in all, advanced and intestinal-type carcinoma patients (P<0.05). Multivariate analysis using the Cox proportional hazards model indicated that patient age, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging and Lauren classification were independent prognostic factors for all gastric carcinomas (P<0.05). Aberrant paxillin expression may be involved in the growth, invasion, metastasis and differentiation of gastric carcinoma. Altered paxillin expression may, therefore, be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinomas.

No abstract

ING5 targets histone acetyltransferase or histone deacetylase complexes for local chromatin remodeling. Its transcriptional regulation and suppressive effects on gastric cancer remain elusive. Luciferase assay, EMSA, and ChIP were used to identify the cis-acting elements and trans-acting factors of the ING5 gene. We analyzed the effects of SAHA on the aggressive phenotypes of ING5 transfectants, and the effects of different ING5 mutants on aggressive phenotypes in SGC-7901 cells. Finally, we observed the effects of ING5 abrogation on gastric carcinogenesis. EMSA and ChIP showed that both SRF (−717 to −678 bp) and YY1 (−48 to 25bp) interacted with the promoter of ING5 and up-regulated ING5 expression in gastric cancer via SRF-YY1-ING5-p53 complex formation. ING5, SRF, and YY1 were overexpressed in gastric cancer, (P&lt;0.05), and associated with worse prognosis of gastric cancer patients (P&lt;0.05). ING5 had positive relationships with SRF and YY1 expression in gastric cancer (P&lt;0.05). SAHA treatment caused early arrest at S phase in ING5 transfectants of SGC-7901 (P&lt;0.05), and either 0.5 or 1.0 μM SAHA enhanced their migration and invasion (P&lt;0.05). The wild-type and mutant ING5 transfectants showed lower viability and invasion than the control (P&lt;0.05) with low CDC25, VEGF, and MMP-9 expression. Gastric spontaneous adenocarcinoma was observed in Atp4b-cre; ING5f/f, Pdx1-cre; ING5f/f, and K19-cre; ING5f/f mice. ING5 deletion increased the sensitivity of MNU-induced gastric carcinogenesis. ING5 mRNA might be a good marker of gastric carcinogenesis, and poor prognosis. ING5 expression was positively regulated by the interaction of SRF-YY1-ING5-p53 complex within the ING5 promoter from −50 bp upstream to the transcription start site. ING5 deletion might contribute to the tumorigenesis and histogenesis of gastric cancer.