Association of metformin and statin uses with the prognosis of colon cancer: a meta-analysis.

BACKGROUND: Metformin and statins are commonly used globally for the treatment of type 2 diabetes mellitus and dyslipidemia, respectively. Recently, multiple novel pathways have been discovered, which may contribute to the treatment of various types of cancer. Several meta-analysis studies have reported that the use of metformin or statins is associated with a lower risk of colon cancer compared to nonusers. In this study, our aim was to perform a meta-analysis and investigate the prognostic roles of these two medications in colon cancer. METHODS: To identify relevant articles, literature searches were performed in the PubMed and Web of Science databases using a combination of keywords related to metformin, statins and colon cancer prognosis until August 2023. The study utilized STATA 12.0 software (Stata Corporation, College Station, Texas, USA) to compute all the hazard ratios (HRs) and 95% confidence intervals (CIs) regarding the association between metformin or statin uses and prognostic-related outcomes. RESULTS: Our analysis revealed that the use of metformin was associated with a significantly lower overall mortality of colon cancer (HR = 0.63; 95% CI = 0.51-0.77; I2 = 94.9%; P < 0.001), as well as lower cancer-specific mortality of colon cancer (HR = 0.68; 95% CI = 0.50-0.94; I2 = 91.9%; P < 0.001). Similarly, the use of statins was also associated with a lower overall mortality of colon cancer (HR = 0.68; 95% CI = 0.60-0.78; I2 = 93.8%; P < 0.001), as well as a lower cancer-specific mortality of colon cancer (HR = 0.74; 95% CI = 0.67-0.81; I2 = 82.2%; P < 0.001). CONCLUSION: Our meta-analysis study suggests that statins and metformin may have potential as adjuvant agents with significant benefits in the prognosis of colon cancer.

Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription.

PURPOSE: Histone deacetylases (HDACs) have been shown to regulate cell cycle, differentiation, and apoptosis of colorectal cancer (CRC) cells, while their roles in drug sensitivity remain unclear. The objectives of the present study were to investigate the effects of HDAC2 on drug resistance of CRC cells. METHODS: We measured the expression of class I HDACs (HDAC1, 2, 3, 8) in CRC and human normal colonic epithelial cells. Additionally, we inhibited HDAC2 via siRNA or overexpressed it via pcDNA/HDAC2 transfection to evaluate its roles in doxorubicin (Dox) sensitivity. RESULTS: Our present study showed HDAC2 was significantly increased in CRC cell lines as compared to human normal colonic epithelial cells. Silencing of HDAC2 can obviously enhance the sensitivity of HCT-116 and SW480 cells to dDox. Further, knockdown of HDAC2 can significantly (p < 0.05) downregulate the expression of ABCB1, while not ABCG2, ABCC1, ABCA1, or ABCC2. Inhibition of HDAC2 decreased ABCB1 promoter activities and the phosphorylation of c-fos and c-Jun, which can directly interact with the ABCB1 promoter and then promote its transcription. Overexpression of HDAC2 by pcDNA/HDAC2 transfection significantly increased the sensitivity of CRC cells to Dox and upregulated the levels of P-gp, p-c-fos, and p-c-Jun. CONCLUSIONS: Our data revealed that HDAC2 can regulate Dox sensitivity of CRC cells by targeting ABCB1 transcription. It suggested that HDAC2 might be an important target for CRC therapy. Further, the combination of HDAC2-specific inhibitor and anticancer drugs including Dox might be an efficiency approach to elevate the treatment outcome of CRC.

Neurokinin-2 receptor polymorphism predicts lymph node metastasis in colorectal cancer patients.

To analyze the single nucleotide polymorphisms (SNPs) of two subtypes of neurokinin (NK) receptors, NK1R and NK2R (also known as TAC1R and TAC2R), in colorectal cancer (CRC), peripheral blood samples were collected from 199 CRC patients. Direct-sequencing was performed to identify the NK1R rs10198644 and NK2R rs4644560 SNPs. Genotype results were correlated with clinical factors. The allele frequencies of NK1R rs10198644 GC, CC and GG were 52, 17 and 31%, respectively, while that of NK2R rs4644560 GC, CC, and GG were 36, 50 and 14%, respectively. Patients with NK2R rs4644560 GC exhibited more positive lymph nodes than those with CC (mean, 2.2 vs. 1.3; P=0.016). Further analysis highlighted that the number of positive lymph nodes was also increased in the NK2R rs4644560 GC/NK1R rs10198644 GG group compared with the NK2R rs4644560 GG/NK1R rs10198644 GG group (mean, 2.2 vs. 0.9; P=0.04). These data suggested that the NK2R rs4644560 GC polymorphism alone or combination with NK1R rs10198644 GG may be a promising prognostic marker of lymph node metastasis in CRC patients.

MicroRNA-194 inhibits the epithelial-mesenchymal transition in gastric cancer cells by targeting FoxM1.

AIM: We hypothesized that miR-194 may control Forkhead box protein M1 (FoxM1) expression in gastric cancer cells and therefore may have therapeutic potential in gastric cancer. METHODS: The expression level of miR-194 was examined using real-time PCR in human gastric cancer and noncancerous gastric tissues, gastric cancer cell and normal gastric mucosal epithelial cell. We examined whether the miR-194 regulates cell migration and invasion, and the epithelial-mesenchymal transition Phenotype by inhibiting FoxM1 in gastric cancer cells. RESULTS: The expression of miR-194 was significantly lower in gastric cancer compared with non-cancerous gastric tissues and cells. Exogenous expression of miR-194 inhibited cell migration, invasion, and the epithelial-mesenchymal transition phenotype in gastric cancer cells. Moreover, we discovered a novel post-transcriptional regulatory mechanism of FoxM1 expression that is mediated by miR-194. CONCLUSION: Our study clearly demonstrates that miR-194 inhibits the acquisition of the EMT phenotype in gastric cancer cells by downregulating FoxM1, thereby inhibiting cell migration and invasion during cancer progression.

SNPs in microRNA-binding sites in the ITGB1 and ITGB3 3'-UTR increase colorectal cancer risk.

The purpose of the study was to investigate the potential associations between single-nucleotide polymorphisms (SNPs) in microRNA (miRNA)-binding sites in the integrin beta-1 (ITGB1) gene and integrin beta-3 (ITGB3) gene 3'-untranslated regions, and colorectal cancer (CRC) susceptibility in a Chinese population. A hospital-based case-control study was performed in 200 patients with CRC and 200 matched healthy donors. Two SNPs in miRNA binding of ITGB1 and ITGB3 genes (rs17468 and rs2317676) were genotyped by polymerase chain reaction-restrict fragment length polymorphism assay. The association between genotypes and CRC risk was evaluated by computing the odds ratio (OR) and 95 % confidence interval (CI) from multivariate unconditional logistic regression analyses. The frequency of the T genotype in ITGB1 rs17468 and G genotype in ITGB3 rs2317676 occurred more frequently in CRC patients than in controls (P < 0.05). We found that CT and TT genotypes of rs17468 were associated with a significantly increased risk of CRC (OR = 1.67, 95 % CI = 1.090-2.559 for CT + TT vs. CC), also the AG and GG genotype in ITGB3 rs2317676 (OR = 1.65, 95 % CI = 1.114-2.458 for AG + GG vs. AA). In conclusion, our results showed that both the ITGB1 rs17468 SNP and ITGB3 rs2317676 SNP were associated with an increased risk of CRC, which suggests that these 2 SNPs might contribute to CRC risk in a Chinese population.

The association between RAD23B Ala249Val polymorphism and cancer susceptibility: evidence from a meta-analysis.

BACKGROUND: A number of studies have investigated associations of genetic variation in RAD23B Ala249Val (rs1805329 C>T) with cancer susceptibility; however, the findings are inconsistent. We performed a meta-analysis to acquire a more precise estimation of the relationship. METHOD: We searched literatures from PubMed, Embase and Web of Science. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between Ala249Val polymorphism and cancer risk. RESULTS: A total of 23 studies consisting of 10837 cases and 13971 controls were included in this meta-analysis. Overall, no significant associations were found between RAD23B Ala249Val polymorphism and cancer risk (Val/Val vs. Ala/Ala: OR = 0.97, 95% CI = 0.75-1.25; Ala/Val vs. Ala/Ala: OR = 1.08, 95% CI = 0.96-1.22; recessive model: OR = 0.93, 95% CI = 0.76-1.14 and dominant model: OR = 1.07, 95% CI = 0.94-1.20). We did not find any significant associations in the further stratification analyses by cancer type, ethnicity and source of control. CONCLUSIONS: Despite some limitations, this meta-analysis indicates that it is unlikely that the RAD23B 249Val/Val polymorphism may contribute to the individual susceptibility to cancer risk. However, further advanced designed studies with larger sample size and different ethnicities should be conducted to confirm our results.

COLORECTAL Polymeric Immunoglobulin Receptor Expression is Correlated with Hepatic Metastasis and Poor Prognosis in Colon Carcinoma Patients with Hepatic Metastasis.

BACKGROUND/AIMS: Increased expression of polymeric immunoglobulin receptor (pIgR) in tumor tissue has been detected in various cancer forms. However, the clinical relevance of pIgR in colon cancer hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of pIgR in patients with colon carcinoma hepatic metastasis after hepatic resection. METHODOLOGY: Genome-wide gene expression analysis was used to evaluate the expression of pIgR in cryopreserved tissue from liver metastases of colon cancer and in the corresponding primary colon cancer tissues from one patient with hepatic metastatic colon cancer. pIgR expression was further confirmed by quantitative real-time PCR in cryopreserved primary colon carcinoma and paired hepatic metastasis tissues from 32 patients with hepatic metastatic colon cancer and by immunohistochemistry in paraffin-embedded primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma who underwent hepatic resection. The relation between pIgR expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive pIgR exspression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. RESULTS: Positive expression of pIgR was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive pIgR expression in colon carcinoma hepatic metastasis than for patients with a negative pIgR expression. Multivariate analysis showed positive-pIgR in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.021). CONCLUSIONS: Positive expression of pIgR was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. pIgR could be a novel predictor for poor prognosis of patients with colon carcinoma hepatic metastasis after hepatic resection.

Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer.

AIM: To investigate the expression of insulin-like growth factor-1 (IGF-1)/insulin-like growth factor-1 receptor (IGF-1R) in colorectal cancer (CRC) tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis. METHODS: Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density (LVD) in 40 CRC specimens. The correlation between IGF-1/IGF-1R and LVD was investigated. Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays. A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo. RESULTS: Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis (r = 0.715 and 0.569, respectively, P < 0.05) and tumor TNM stage (r = 0.731 and 0.609, P < 0.05). A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis (r = 0.405, P < 0.05). A positive correlation was found between LVD and IGF-1R expression (r = 0.437, P < 0.05). Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells. In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts. CONCLUSION: IGF-1/IGF-1R signaling induces tumor-associated lymphangiogenesis and contributes to lymphatic metastasis of CRC.

Total mesorectal excision for rectal cancer: laparoscopic versus open approach.

AIMS AND BACKGROUND: To evaluate the oncologic safety of laparoscopic total mesorectal excision for rectal cancer. Methods and study design. Patients who underwent laparoscopic (n = 256) or open (n = 173) total mesorectal excision for rectal cancer between June 2005 and June 2011 were included. Long-term survival operative data and postoperative recovery were retrospectively reviewed from a prospectively collected database. RESULTS: No significant difference was found between the two groups in terms of age, sex, tumor stage and preoperative comorbidities. Twelve patients were converted to open procedures. Differences were found in blood loss (55 ± 14.1 vs 152 ± 29.2 ml P <0.05), infection of incision (3.1% vs 12.7%, P <0.05) and postoperative stay (8.1 ± 3.0 vs 12.4 ± 6.3 days, P <0.05). Both groups were comparable regarding lymph node clearance specimen length and distal margin. There was no significant difference in overall survival between the two groups by the life-table method. However, operative time in the laparoscopic group was longer than in the open group (168 ± 27.6 vs 141 ± 21.9 min, P <0.05). CONCLUSIONS: Laparoscopic total mesorectal excision for rectal cancer offers oncologic results similar to those obtained with the open procedure with a favorable short-term outcome. Continued use of the procedure in these patients is supported.