Allulose mitigates chronic enteritis by reducing mitochondria dysfunction via regulating cathepsin B production.

Metabolic changes have been linked to the development of inflammatory bowel disease (IBD), which includes colitis. Allulose, an endogenous bioactive monosaccharide, is vital to the synthesis of numerous compounds and metabolic processes within living organisms. Nevertheless, the precise biochemical mechanism by which allulose inhibits colitis remains unknown. Allulose is an essential and intrinsic protector of the intestinal mucosal barrier, as it maintains the integrity of tight junctions in the intestines, according to the current research. It is also important to know that there is a link between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), chemically-induced colitis in rodents, and lower levels of allulose in the blood. Mice with colitis, either caused by dextran sodium sulphate (DSS) or naturally occurring colitis in IL-10-/- mice, had less damage to their intestinal mucosa after being given allulose. Giving allulose to a colitis model starts a chain of reactions because it stops cathepsin B from ejecting and helps lysosomes stick together. This system effectively stops the activity of myosin light chain kinase (MLCK) when intestinal epithelial damage happens. This stops the breakdown of tight junction integrity and the start of mitochondrial dysfunction. To summarise, the study's findings have presented data that supports the advantageous impact of allulose in reducing the advancement of colitis. Its ability to stop the disruption of the intestinal barrier enables this. Therefore, allulose has potential as a medicinal supplement for treating colitis.

SHF confers radioresistance in colorectal cancer by the regulation of mitochondrial DNA copy number.

Altered mitochondrial function contributes greatly to pathogenesis and progression of colorectal cancer. In this study, we report a functional pool of Src homology 2 domain-containing F (SHF) in mitochondria controlling the response of colorectal cancer cells to radiation therapy. We found that elevated expression of SHF in cancer cells is essential for promoting mitochondrial function by increasing mitochondrial DNA copy number, thus reducing the sensitivity of colorectal cancer cells to radiation. Mechanistically, SHF binds to mitochondrial DNA and promotes POLG/SSBP1-mediated mitochondrial DNA synthesis. Importantly, SHF loss-mediated radiosensitization was phenocopied by depletion of mitochondrial DNA. Thus, our data demonstrate that mitochondrial SHF is an important regulator of radioresistance in colorectal cancer cells, identifying SHF as a promising therapeutic target to enhance radiotherapy efficacy in colorectal cancer.

FKBP4 regulates 5-fluorouracil sensitivity in colon cancer by controlling mitochondrial respiration.

Mitochondrial respiration and metabolism play a key role in the pathogenesis and progression of colon adenocarcinoma (COAD). Here, we report a functional pool of FKBP4, a co-chaperone protein, in the mitochondrial intermembrane space (IMS) of colon cancer cells. We found that IMS-localized FKBP4 is essential for the maintenance of mitochondrial respiration, thus contributing to the sensitivity of COAD cells to 5-fluorouracil (5-FU). Mechanistically, FKBP4 interacts with COA6 and controls the assembly of the mitochondrial COA6/SCO1/SCO2 complex, thereby governing COA6-regulated biogenesis and activity of mitochondrial cytochrome c oxidase (complex IV). Thus, our data reveal IMS-localized FKBP4 as a novel regulator of 5-FU sensitivity in COAD, linking mitochondrial respiration to 5-FU sensitivity in COAD.

A novel mitochondria-related gene signature for controlling colon cancer cell mitochondrial respiration and proliferation.

Colon cancer cells rely on mitochondrial respiration as major source of energy for supporting their proliferation and invasion, thus promoting colon cancer malignancy and progression. In this study, we comprehensively investigated the prognostic significance of mitochondria-related genes in colon cancer and identified the hub genes that control colon cancer cell mitochondrial respiration and proliferation. We first systematically evaluated the prognostic significance of differentially expressed mitochondria-related genes in colon cancer specimens. Furthermore, a protein-protein interaction network was constructed to explore the hub genes. Eventually, five hub genes were identified, namely, POLG, FASTK, MRPS5, AARS2, and VARS2. Functional analyses showed that all these five hub genes are essential for maintaining mitochondrial respiration and proliferation of colon cancer cells. Mechanistic studies revealed the roles of these five hub genes in modulating mitochondrial DNA expression, that in turn influence mitochondrial respiration. In summary, our study demonstrated that POLG, FASTK, MRPS5, AARS2, and VARS2 may potentially serve as prognostic biomarkers and therapeutic targets for colon cancer.

Revealing potential immunotherapy targets through analysis of a ceRNA network in human colon adenocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a special type of human colon adenocarcinoma (COAD) that responds well to immunotherapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which are important members of competing endogenous RNAs (ceRNAs) networks, are involved in the tumorigenesis and development of MSI-H COAD. This study aimed to establish a ceRNA network for MSI in COAD to identify targets and prognostic markers that may explain the effects of immunotherapy. METHODS: COAD sequencing data were extracted from The Cancer Genome Atlas (TCGA), after which differentially expressed miRNAs, lncRNAs, and mRNAs were determined according to microsatellite status. After building a network based on the ceRNA hypothesis, the relationships between microsatellite status and clinical features were explored. Biological processes in the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were analyzed for specific miRNAs, lncRNAs, and mRNAs. Survival analysis was used to identify potential biomarkers. RESULTS: Based on the inclusion criteria, a total of 363 COAD samples were obtained from TCGA. Strict screening criteria were used to identify differentially expressed RNAs in the MSI-H and microsatellite-stable groups, with 82 miRNAs, 1,280 lncRNAs, and 2121 mRNAs obtained (fold change >2, false discovery rate <0.01). Based on the RNA interaction mechanism, a miRNA-lncRNA-mRNA network was constructed, through which a subnetwork composed of 5 miRNAs was discovered. hsa-miR-31-5p, hsa-miR-302a-3p, hsa-miR-302b-3p, hsa-miR-302d-3p, hsa-miR-3619-5p and the RNAs interaction with them have the potential to become novel targets to change the effect of existing immunotherapy. GO and KEGG analyses showed that these differentially expressed miRNAs, lncRNAs, and mRNAs may play key roles in tumorigenesis, tumor development, and drug efficacy, with natural killer cells potentially becoming the next emerging targets for immunotherapy enhancement. Moreover, survival analysis identified 10 lncRNAs as potential survival markers. CONCLUSIONS: This study identified novel immunotherapy targets and revealed potential biomarkers for COAD according to microsatellite status.

NT5DC2 knockdown inhibits colorectal carcinoma progression by repressing metastasis, angiogenesis and tumor-associated macrophage recruitment: A mechanism involving VEGF signaling.

Colorectal cancer (CRC) is one of the most commonly diagnosed tumors among human worldwide. Angiogenesis and tumor-associated macrophage (TAM) recruitment are closely associated with CRC development. Nevertheless, the mechanisms revealing CRC progression are still not fully understood. 5'-Nucleotidase domain containing 2 (NT5DC2), a member of the NT5DC family, modulates various cellular events to mediate tumor growth, and thus serves as a disgnostic biomarker. Here, we explored the potential of NT5DC2 on tumor progression in CRC. We first found that NT5DC2 expression was significantly up-regulated in CRC tissues and cell lines. CRC patients with higher NT5DC2 expression showed poor overall survival. Furthermore, CRC cell lines stably transfected with shNT5DC2 lentivirus plasmids exhibited markedly reduced cell proliferation, migration and invasion compared with the negative control group. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) expression levels were remarkably reduced in CRC cells with NT5DC2 deletion, along with evidently reduced tube formation in the HUVECs cultured in the collected conditional medium. The expression levels of CC chemokine ligand 2 (CCL2) and its receptor CCR2 were found to be greatly down-regulated in CRC cells transfected with shNT5DC2. Moreover, NT5DC2 knockdown markedly suppressed the activation of protein kinase-B/nuclear transcription factor κB (AKT/NF-κB) signaling in CRC cells. Furthermore, we found that NT5DC2 deletion obviously reduced the TAM recruitments through suppressing CCL2/CCR2 and AKT/NF-κB signaling pathways. Intriguingly, our in vitro experiments demonstrated that VEGF reduction was necessary for shNT5DC2-inhibited cell proliferation, migration, invasion, angiogenesis and TAM recruitment. In vivo studies also confirmed that NT5DC2 knockdown effectively reduced the tumor growth and VEGF expression in a xonegraft mouse model with CRC. Lung metastasis of CRC cells was also hindered by NT5DC2 deletion in vivo. Collectively, our results indicated a previously unrecognized NT5DC2/VEGF/CCL2 axis involved in CRC development and metastasis.

Outcomes of radiation therapy for resectable M0 gastric cancer.

BACKGROUND: The role of radiaotion therapy in resectable gastric cancer patients without distant metastases remains controversial. This retrospective analysis was performed to identify whether resectable gastric cancer patients without distant metastases might benefit from radiation. RESULTS: The results of the Kaplan-Meier analysis and log-rank test showed that a total of 3309 patients had a MST of 29.0 months, a 1-year survival rate of 74.7%, and a 3-year survival rate of 45.5%. Among them, the MST of the "RPS" group and the "RAS" group were significantly longer compared with that of the "No Radiation" group (32.7vs 32.9 vs 25.3 months, P < 0.05). The 1-year survival rates were 83.7%, 83.5% and 65.6% for the "RPS", "RAS" and "No radiation" groups, respectively (P < 0.05) and the 3-year survival rates were 52.6%, 63.6% and 44.9%, respectively (P < 0.05). The multivariate Cox proportional hazard regression analysis showed that radiation was an independent prognostic factor. MATERIALS AND METHODS: A total of 5744 patients from the SEER database who were initially diagnosed with histologically confirmed gastric cancer without distant metastases from 2010 to 2013 were included. Patients were divided into three groups as follows: patients who underwent radiation after surgery ("RAS" group), patients who underwent radiation prior to surgery ("RPS" group) and patients who did not undergo radiation ,only surgery performed ("No radiation'"group). CONCLUSIONS: This retrospective analysis demonstrated that "RPS" or "RAS"alone were independent prognostic factors for survival improvement in selected gastric cancer patients without distant metastases.

[Analysis of gastric gastrointestinal stromal tumors in Shandong Province: a midterm report of multicenter GISSG1201 study].

OBJECTIVE: To summarize the treatment status of gastric gastrointestinal stromal tumor (GIST) in Shandong province,by analyzing the clinicopathological features and prognostic factors. METHODS: Clinicopathological and follow-up data of 1 165 patients with gastric GIST between January 2000 and December 2013 from 23 tertiary referral hospitals in Shandong Province were collected to establish a database. The risk stratification of all cases was performed according to the National Institutes of Health(NIH) criteria proposed in 2008. Kaplan-Meier method was used to calculate the survival rate. Log-rank test and Cox regression model were used for univariate and multivariate prognostic analyses. RESULTS: Among 1 165 cases of gastric GIST, 557 were male and 608 were female. The median age of onset was 60 (range 15-89) years. Primary tumors were located in the gastric fundus and cardia in 623 cases(53.5%), gastric body in 346 cases(29.7%), gastric antrum in 196 cases(16.8%). All the cases underwent resection of tumors, including endoscopic resection (n=106), local resection (n=589), subtotal gastrectomy(n=399), and total gastrectomy(n=72). Based on the NIH risk stratification, there were 256 cases (22.0%) at very low risk, 435 (37.3%) at low risk, 251 cases (21.5%) at intermediate risk, and 223 cases (19.1%) at high risk. A total of 1 116 cases(95.8%) were followed up and the median follow-up period was 40 (range, 1-60) months. During the period, 337 patients relapsed and the median time to recurrence was 34 (range 1-60) months. The 1-, 3-, and 5-year survival rates were 98.6%, 86.1% and 73.4%, respectively. The 5-year survival rates of patients at very low, low, intermediate, and high risk were 93.1%, 85.8%, 63.0% and 42.3% respectively, with a statistically significant difference (P=0.000). Multivariate analysis showed that primary tumor site (RR=0.580, 95%CI:0.402-0.835), tumor size (RR=0.450, 95%CI:0.266-0.760), intraoperative tumor rupture(RR=0.557, 95%CI:0.336-0.924), risk classification (RR=0.309, 95%CI:0.164-0.580) and the use of imatinib after surgery (RR=1.993, 95%CI:1.350-2.922) were independent prognostic factors. CONCLUSIONS: The choice of surgical procedure for gastric GIST patients should be based on tumor size. All the routine procedures including endoscopic resection, local excision, subtotal gastrectomy and total gastrectomy can obtain satisfactory curative outcomes. NIH classification has a high value for the prediction of prognosis. Primary tumor site, tumor size, intraoperative tumor rupture, risk stratification and postoperative use of imatinib are independent prognostic factors in gastric GIST patients.

Gallbladder perforation: a rare complication of postoperative chemotherapy of gastric cancer.

A middle-aged man presented 1 day after being discharged from hospital with completing the first course of postoperative chemotherapy. He suffered a sudden persistent high fever and chills. It was noted that he had a history of a total gastrectomy (with D2 lymphadenectomy) 1 month ago. His admission bloods revealed total bilirubin was 142.2 umol/L, indirect bilirubin of 107.6 umol/L and white cell count of 20.05×10(9)/L. A color doppler ultrasound scan confirmed fluid and gas around liver and hilus lienis while the gallbladder cannot be detected. During Computed Tomography (CT) guided puncture positioning technology and setting a three-channel tube, about 400 ml of foul smell hazel turbid liquid was drained out. He was diagnosed as gallbladder perforation and he was underwent conservative treatment consist of drainage, banning diet, total parenteral nutrition and intravenous antibiotics. Then he recovered well within the subsequent 10 days and was discharged.

RLIP76 blockade by siRNA inhibits proliferation, enhances apoptosis, and suppresses invasion in HT29 colon cancer cells.

RLIP76, a multidomain protein which is a downstream effector of the small GTP ases RalA and RalB, is known to play a role in biological activities in a variety of malignant cancer cells. However, little study has been done on the role of RLIP76 in CRC. In this study, a RLIP76-targeted siRNA-containing vector was used to investigate the effect of RLIP76 knockdown on cellular functions in human CRC cell line HT29. Quantitative RT-PCR and Western blot analysis revealed that the expression levels of RLIP76 mRNA and protein in HT29 cells were significantly suppressed after transfection. Our results indicated that RLIP76 downregulation in HT29 CRC cells suppressed cell growth, enhanced cell apoptosis, induced cell cycle arrest, and inhibited cell invasion by decreasing MMP2 expression. Although the mechanisms through which RLIP76 regulates the cellular functions needs further investigation, our results indicate that RLIP76 may represent as a potential target of gene therapy for CRC treatment.

[Phosphorylation status of ASPP2 modulates p53 apoptotic function in oxaliplatin-induced apoptosis of colorectal cancer HCT116 cells].

OBJECTIVE: To investigate the role of apoptosis stimulating protein 2 of p53 (ASPP2) phosphorylation status in the regulation of ASPP2-p53 apoptotic pathway activity. METHODS: Cells were individually transfected with green fluorescent protein (GFP)-encoding vector, constitutively non-phosphorylatable ASPP2 mutant-ASPP2 (Am)-encoding vector, and wild type ASPP2 (Aw)-encoding vector) plasmids, respectively, to make them overexpressing phosphorylated and non-phosphorylated ASPP2 proteins, respectively. Cell apoptosis was induced by oxaliplatin. The apoptosis rate of cells was determined by flow cytometry after staining with FITC-conjugated annexin V and PI. ASPP2 protein level and its phosphorylation status were observed by Western blot. The interaction between ASPP2 and p53 was observed by immunoprecipitation assay. RESULTS: Oxaliplatin induced cell apoptosis and caused phosphorylation of ASPP2 at ser92/ser361 in the HCT116 cells. The apoptosis rate of Aw and Am plasmids-transfected cells were (3.8 ± 1.0)% and (3.9 ± 1.2)% respectively, statistically with a non-significant difference (P > 0.05) in comparison with that of the GFP plasmid-transfected cells [(4.0 ± 0.8)%]. After oxaliplatin treatment, the apoptosis rate of Aw plasmid-transfected cells was (46.7 ± 3.9)%, significantly higher than that of the Am and GFP plasmid-transfected cells [(40.1 ± 10.2)% and (37.1 ± 6.9)%, respectively, P < 0.05], however, there was no statistically significant difference (P > 0.05) between Am and GFP plasmid-transfected cells. These results indicate that phosphorylated ASPP2 promoted the oxaliplatin-induced apoptosis of HCT116 cells through a p53-dependent pathway. Phosphorylation status of ASPP2 influenced its binding activity to p53. CONCLUSION: Phosphorylation status of ASPP2 modulates p53 apoptotic function in oxaliplatin-induced apoptosis of colorectal cancer HCT116 cells.

Effect of BRMS1 on tumorigenicity and metastasis of human rectal cancer.

Breast cancer metastasis suppressor gene-1 (BRMS1) is newly discovered tumor metastasis gene, which has been reported to play an important role in the progression of human tumor. However, its role in rectal cancer has never been investigated. In this present study, we evaluated the associated of BRMS1 with colorectal cancer, its value in prognosis, and its role in metastasis of rectal cancer. BRMS1 expression examined in 80 patients and the role of BRMS1 in metastasis was studied using mice model. Our results showed that BRMS1 expression was significantly associated with clinicopathological parameters in rectal cancer patients and overexpression of BRMS1 in rectal cancer xenograft led to decreased growth, invasiveness and metastasis. Our findings indicate that high expression of BRSM1 in rectal cancer plays an essential role in tumor progression.

Icariin enhances radiosensitivity of colorectal cancer cells by suppressing NF-κB activity.

Radiation therapy is an integral part of the current therapeutic protocols in colorectal cancer. However, only a small proportion of the patients achieved complete pathological response because of the treatment-induced resistance to radiation. Previous studies have shown that radioresistance is associated with NF-κB activation and that suppression of NF-κB could potentiate the response of colorectal cancer cells to radiotherapy. Icariin, a natural flavonoid, has been shown to suppress NF-κB activity. The present study was carried out to investigate whether icariin could act as a radiosensitizer in colorectal cancer cells and murine model of the colorectal cancer. We also sought to understand the mechanisms underlying the icariin-mediated radiosensitization. Our results showed that icariin enhanced the radiation-mediated anti-proliferative effect both in vitro and in vivo. Further, icariin exerted the anti-proliferative and/or pro-apoptotic effect possibly, by: (1) inducing the cell arrest in G2/M phases of the cell cycle, or by (2) downregulating NF-κB and the anti-apoptotic gene products monitored by this transcription factor. Icariin could also potentiate the efficacy of radiotherapy in the murine model of colorectal cancer. Taken together, these results suggest that the use of icariin may provide with a new approach for sensitizing the radiotherapy in colorectal cancer.