ABSTRACT
Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is upregulated in various human cancers and reportedly has oncogenic activities. However, the functional roles of AGR2 and its regulation in colorectal cancer (CRC) remain unclear. Here, we showed that AGR2 promoted CRC tumorigenesis and progression in vitro and in vivo and acted as an independent prognostic factor of poor outcome. AGR2 was negatively regulated by DNA methyltransferase 3a (DNMT3a) through directly methylating AGR2 promoter and by a DNMT3a-SPRY2-miR-194 axis. Moreover, AGR2 mediated the resistance to 5-Aza-2'-deoxycytidine (5-Aza) treatment. Knockdown of AGR2 improved the therapeutic effect of 5-Aza in human CRC xenograft tumor model. Thus, our work supports AGR2's oncogenic role in CRC, reveals DNMT3a-mediated epigenetic modulation on AGR2 promoter, and uncovers a new DNMT3a signaling module controlling expression of AGR2. Upregulated AGR2 offset 5-Aza mediated epigenetic therapy. This work might provide potential targets for clinical anti-cancer therapy.
Subject(s)
Azacitidine/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , Drug Resistance, Neoplasm/genetics , Mucoproteins/genetics , Oncogene Proteins/genetics , Caco-2 Cells , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Line , Cell Line, Tumor , DNA Methyltransferase 3A , Disease Progression , Epigenesis, Genetic/genetics , Gene Expression Regulation, Neoplastic/genetics , HEK293 Cells , HT29 Cells , Humans , Prognosis , Promoter Regions, Genetic/genetics , Signal Transduction/genetics , Up-Regulation/geneticsABSTRACT
BACKGROUND: Major limitations of conventional 2-dimensional (2D) laparoscopy are a lack of depth perception and spatial orientation. Three-dimensional (3D) laparoscopy was developed to overcome the limitations of the 2D technique. However, it has not been widely accepted due to a lack of conclusive evidence of benefit. The aim of this study was to evaluate the effect of 3D laparoscopy on the operative performance during elective laparoscopic right colectomy. METHODS: A total of 58 consecutive patients underwent laparoscopic colectomy for right-sided colon cancer by a single experienced surgeon between January 2014 and July 2015. Patients were classified into 2 groups according to the vision system of laparoscopy: 27 patients were operated by 3D laparoscopy (3D group, n=27) and 31 patients were performed by 2D laparoscopy (2D group, n=31). Data of these patients were collected and analyzed retrospectively. RESULTS: The operative time was significantly shorter in the 3D group than in the 2D group (130.5±27.6 vs. 152.2±28.9 min, P=0.005). There was no significant difference in blood loss in the 3D group when compared with the 2D group. There was no operative mortality in the 2 groups. The number of lymph nodes resected was similar in both groups. Time to pass the first flatus and postoperative hospital stay showed no significant differences between the 2 groups. The postoperative complication rate for the 3D and the 2D groups were similar: 14.8% (4/27) and 9.7% (3/31), respectively. CONCLUSIONS: 3D laparoscopy appears to reduce the performance time of laparoscopic colectomy when compared with 2D laparoscopy. Further studies are required to address the role of the 3D vision system in laparoscopic colectomy.
Subject(s)
Colectomy/methods , Colonic Neoplasms/surgery , Laparoscopy/methods , Adult , Aged , Elective Surgical Procedures/methods , Female , Humans , Imaging, Three-Dimensional , Length of Stay , Male , Middle Aged , Operative Time , Postoperative Complications/etiology , Treatment OutcomeABSTRACT
Maresin 1 (MaR 1) was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1ß, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb) and mitogen-activated protein kinases (MAPKs) in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway.
Subject(s)
Docosahexaenoic Acids/pharmacology , Liver/pathology , Alanine Transaminase/blood , Animals , Antioxidants/metabolism , Aspartate Aminotransferases/blood , Carbon Tetrachloride , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cyclooxygenase 2/metabolism , Cytokines/blood , Docosahexaenoic Acids/administration & dosage , Glutathione/metabolism , Hep G2 Cells , Humans , Inflammation Mediators/metabolism , Liver/drug effects , Male , Mice, Inbred BALB C , Mitogen-Activated Protein Kinases/metabolism , NF-KappaB Inhibitor alpha/metabolism , Nitric Oxide Synthase Type II/metabolism , Oxidative Stress/drug effects , Peroxidase/metabolism , Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Thiobarbituric Acid Reactive Substances/metabolism , Transcription Factor RelA/metabolismABSTRACT
BACKGROUND: SALL4 is a novel oncogene mediating tumorigenesis in multiple carcinomas. However, its actual role and mechanisms participating in the development of colorectal cancer remains unclear. METHODS: Immunohistochemical staining and Western blot were conducted to detect the expression of SALL4 and other molecules. siRNA of SALL4 was transfected to silence SALL4 expression in Caco-2 cell line. Flow cytometry was used for cell cycle and apoptosis analysis. Wound healing and transwell assay were used for invasion test. CCK-8 test was employed for cell proliferation and drug sensitivity assessment. RESULTS: By inhibition of SALL4 expression, the proliferation, invasiveness and drug resistance were dramatically reduced while apoptosis rate was up-regulated. Gli1 was found to decrease its expression in SALL4 silencing cells. Moreover, the inhibition on tumorigenesis of Caco-2 by SALL4 silencing was antagonized by Gli1 up-regulation, suggesting Gli1 as a downstream target of SALL4 in cancer development. CONCLUSION: SALL4 inhibition limited oncogenesis on colorectal cancer by reducing Gli1 expression.
Subject(s)
Carcinogenesis/genetics , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Invasiveness/genetics , Transcription Factors/genetics , Apoptosis/genetics , Caco-2 Cells , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Humans , Neoplasm Invasiveness/pathology , Transcription Factors/metabolism , Zinc Finger Protein GLI1ABSTRACT
Synchronous colorectal carcinoma defines as multiple malignant lesions presented in a single patient at initial diagnosis. We report a case of triple synchronous colorectal carcinoma without related familial history. Preoperative computed tomography (CT) scan and endoscopic examination suggested multiple malignant lesions occurred in separate segments of colon. Then we performed laparoscopic total colectomy and ileorectal anastomosis with a J-type pouch. Post operative pathological examination confirmed the malignant characteristics of the triple lesions. The mini review summarizes the clinicopathological and molecular features of synchronous colorectal carcinoma based on current literatures. It appears to probably have significant distinctions with solitary tumors in terms of pathological type, primary locations and microsatellite instability.
Subject(s)
Adenocarcinoma/pathology , Colorectal Neoplasms/pathology , Neoplasms, Multiple Primary/pathology , Humans , Male , Middle AgedABSTRACT
Sall4 is a novel oncogene found upregulated in several malignancies including colon cancer. However, its upstream regulatory miRNA is still undefined. miR-219-5p is regarded as a tumor-related miRNA in cancer research. Nevertheless, its actual role of whether inhibiting or promoting tumorigenesis is unclear in colon cancer. Potential interaction between Sall4 and miR-219-5p is predicted by TargetScan. CCK-8 test was used for evaluation of cell proliferation and cell survival rates. Western blot analysis and real-time PCR were applied for detection of target molecules. Luciferase assay was a direct confirmation of mutual interaction. Wound healing assay and transwell assay were conducted for cell migration and invasion tests. Flow cytometry was used for cell apoptosis analysis. Tissue specimens and cell lines were explored for miR-219-5p inhibition on colon cancer proliferation, migration, invasion, apoptosis and drug resistance by targeting Sall4. The results show that miR-219-5p inhibited carcinogenesis of colon cancer by targeting oncogene Sall4.
Subject(s)
Colonic Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , MicroRNAs/genetics , Transcription Factors/biosynthesis , Apoptosis/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Humans , MicroRNAs/biosynthesis , Neoplasm Invasiveness/genetics , Transcription Factors/geneticsABSTRACT
It has previously been reported that high mobility group box chromosomal protein 1 (HMGB1) is overexpressed in the majority of gastric adenocarcinoma cell types, and that HMGB1 can be released into the extracellular matrix from stressed or necrotic cancer cells. HMGB1 is considered to promote cell proliferation and invasion in gastric adenocarcinoma cells. Furthermore, in a number of cancer cell types, HMGB1 has been reported to promote autophagy and inhibit anticancer druginduced apoptosis, which has been identified as an important mechanism in the development of multidrug resistance (MDR). However, there have been no studies on the effects of HMGB1 on expression of the MDRrelated transporter proteins in gastric adenocarcinoma. In the present study, extracellular HMGB1 increased the expression levels of P-glycoprotein (P-gp) at the pre-transcriptional and posttranscriptional levels in the human gastric adenocarcinoma cell lines, SGC7901, MKN28 and AGS, as detected by quantitative polymerase chain reaction and western blot assays. MTT and apoptosis assays were also performed and it was demonstrated that extracellular HMGB1 subsequently enhanced resistance to the Pgprelated drugs, adriamycin and vincristine. In brief, this study demonstrated that extracellular HMGB1 may promote drug resistance to adriamycin and vincristine by upregulating Pgp in human gastric adenocarcinoma cells.