Activation of IRE1α-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma.

Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1α-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1α-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1α was determined to be an independent predictor of overall survival as higher expression of IRE1α in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1α were applied to determine the molecular effects of IRE1α in CRC cells. The silencing of IRE1α inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1α in turn promoted cell proliferation and invasion. IRE1α-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1α-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1α could be employed as a novel prognostic marker and a promising therapeutic target for CRC.

[Antitumor effect of capsaicin on colorectal carcinoma xenograft in nude mice].

OBJECTIVE: To evaluate the effect of capsaicin on nude mice xenografted with colorectal carcinoma cells, and to explore its mechanism of action. METHODS: A nude mouse model of colorectal cancer was established by subcutaneous inoculation of human colorectal carcinoma HT-29 cells. Terminal deoxynucleotidyl transferase-mediated nicked labeling assay (TUNEL) was undertaken to detect the cell proliferation and apoptosis in the xenograft tissue in nude mice. Immunohistochemical (IHC) staining and Western blot were used to detect the expression of HSP27, Cyt-C and active caspase-3. RESULTS: The tumor growth of the groups C10 and C20 was significantly slower than that of the group NS. The integrated optical density (IOD) of both the group C5 (2532.14 ± 578.11) and group C10 (6364.03 ± 1137.98) was significantly higher than that of the group NS (760.12 ± 238.05), (P < 0.05). The integrated optical density (IOD) of the group C20 was (15743.96 ± 1855.95), significantly higher than that of the groups C10, C5 and NS (all were P < 0.01). Immunohistochemistry showed that the cytoplasmic expression of HSP27 was strongly positive in the group NS, and significantly reduced with the increasing dose of capsaicin in the treated groups. The expression of active caspase-3 and Cyt-C in the group NS was weakly positive, and was significantly increased with the increasing dose of capsaicin in the groups C5 and C10 (P < 0.05), and the expression of active caspase-3 and Cyt-C of the group C20 was significantly higher than that of the groups C5, C10 and NS (P < 0.01). Western blot analysis showed that both the expressions of HSP27 of the group C5 (0.73 ± 0.05) and the group C10 (0.41 ± 0.03) were significantly lower than that of the group NS (P < 0.05). The expression of HSP27 of the group C20 (0.22 ± 0.06) was significantly lower than that of the groups C5, C10 and NS (P < 0.01). The expressions of active-caspase-3 and Cyt-C in the group C5 were (2.57 ± 0.34) and (2.03 ± 0.38), significantly higher than those of the group NS (P < 0.05). The expressions of active-caspase-3 and Cyt-C in the group C10 were (4.23 ± 0.45) and (3.13 ± 0.44), also significantly higher than those of the group NS (P < 0.05). The expressions of active-caspase-3 and Cyt-C in the group C20 were (5.78 ± 0.48) and (4.92 ± 0.52), significantly higher than those of the group C5, C10 and NS (P < 0.01). TUNEL analysis showed that there was a significant difference of cell apoptosis in comparison of each two groups. The higher dose of capsaicin was used, the more apoptosis was observed. CONCLUSIONS: Capsaicin can significantly inhibit the tumor growth and induce cell apoptosis in the colorectal carcinoma xenograft in nude mice. Its mechanism of action is possibly related with the down-regulation of HSP27 expression and up-regulation of expression of active caspase-3 and Cyt-C in the colorectal carcinoma xenograft in nude mice.

Metabolic Syndrome, as Defined Based on Parameters Including Visceral Fat Area, Predicts Complications After Surgery for Rectal Cancer.

BACKGROUND/OBJECTIVES: Metabolic syndrome (MetS) has become a major public health problem. However, few studies have examined the impact of MetS on the postoperative complications of colorectal cancer and the conclusions remain controversial. The present study aimed to investigate whether MetS, as defined based on visceral fat area (VFA) instead of BMI or waist circumference, would predict complications after surgery for rectal cancer. SUBJECTS/METHODS: We conducted a retrospective study of patients who underwent surgery for rectal cancer at our department between January 2013 and August 2018. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. A receiver operating characteristic curve analysis was used to determine the gender-specific cut-off values for VFA. RESULTS: A total of 381 patients were included in the study. The optimal cut-off values for VFA were 117.9 cm2 for men and 76.9 cm2 for women, and 153 patients were diagnosed as having MetS. The rate of postoperative complication was significantly higher in the MetS group than that in the non-MetS group (34.6% versus 15.8%, P < 0.001). The multivariate logistic regression analysis demonstrated that MetS (OR 3.712, P < 0.001), NRS 2002 scores ≥ 3 (OR 2.563, P = 0.001), and tumor located at the lower 1/3 (OR 3.290, P = 0.001) were independent risk factors for complications after surgery for rectal cancer. CONCLUSION: Metabolic syndrome, as defined based on parameters including visceral fat area, was an independent risk factor for complications after surgery for rectal cancer.