Orally Administrated Hydrogel Harnessing Intratumoral Microbiome and Microbiota-Related Immune Responses for Potentiated Colorectal Cancer Treatment.

The intestinal and intratumoral microbiota are closely associated with tumor progression and response to antitumor treatments. The antibacterial or tumor microenvironment (TME)-modulating approaches have been shown to markedly improve antitumor efficacy, strategies focused on normalizing the microbial environment are rarely reported. Here, we reported the development of an orally administered inulin-based hydrogel with colon-targeting and retention effects, containing hollow MnO2 nanocarrier loaded with the chemotherapeutic drug Oxa (Oxa@HMI). On the one hand, beneficial bacteria in the colon specifically metabolized Oxa@HMI, resulting in the degradation of inulin and the generation of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in modulating microbiota and stimulating immune responses. On the other hand, the hydrogel matrix underwent colon microbiota-specific degradation, enabling the targeted release of Oxa and production of reactive oxygen species in the acidic TME. In this study, we have established, for the first time, a microbiota-targeted drug delivery system Oxa@HMI that exhibited high efficiency in colorectal cancer targeting and colon retention. Oxa@HMI promoted chemotherapy efficiency and activated antitumor immune responses by intervening in the microbial environment within the tumor tissue, providing a crucial clinical approach for the treatment of colorectal cancer that susceptible to microbial invasion.

Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice.

BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.

Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Laser-Activatable In Situ Vaccine Enhances Cancer-Immunity Cycle.

The immune response in cancer reflects a series of carefully regulated events; however, current tumor immunotherapies typically address a single key aspect to enhance anti-tumor immunity. In the present study, a nanoplatform (Fe3 O4 @IR820@CpG)-based immunotherapy strategy that targets the multiple key steps in cancer-immunity cycle is developed: 1) promotes the release of tumor-derived proteins (TDPs), including tumor-associated antigens and pro-immunostimulatory factors), in addition to the direct killing effect, by photothermal (PTT) and photodynamic therapy (PDT); 2) captures the released TDPs and delivers them, together with CpG (a Toll-like receptor 9 agonist) to antigen-presenting cells (APCs) to promote antigen presentation and T cell activation; 3) enhances the tumor-killing ability of T cells by combining with anti-programmed death ligand 1 antibody (α-PD-L1), which collectively advances the outstanding of the anti-tumor effects on colorectal, liver and breast cancers. The broad-spectrum anti-tumor activity of Fe3 O4 @IR820@CpG with α-PD-L1 demonstrates that optimally manipulating anti-cancer immunity not singly but as a group provides promising clinical strategies.

Cx43-Delivered miR-181b Negatively Regulates Sirt1/FOXO3a Signalling Pathway-Mediated Apoptosis on Intestinal Injury in Sepsis.

INTRODUCTION: Gap junctions can transmit signals between cells, including miRNAs, leading to the amplification of adjacent cell damage. No previous study has addressed gap junctions and miRNAs in sepsis because the internal mechanism of sepsis-induced intestinal injury is complex. Therefore, we studied the relationship between connexin43 (Cx43) and miR-181b and provided a research direction for further study of sepsis. METHODS: A mouse caecal ligation and puncture method was used to construct a mouse sepsis model. Firstly, damage to intestinal tissues at different time points was analysed. The levels of Cx43, miR-181b, Sirt1, and FOXO3a in intestinal tissues and the transcription and translation of the apoptosis-related genes Bim and puma, which are downstream of FOXO3a were analysed. Secondly, the effect of Cx43 levels on miR-181b and Sirt1/FOXO3a signalling pathway activity was explored by using the Cx43 inhibitor heptanol. Finally, luciferase assays were used to determine miR-181b binding to the predicted target sequence. RESULTS: The results show that during sepsis, intestinal injury becomes increasingly worse with time, and the expression of Cx43 and miR-181b increase. In addition, we found that heptanol could significantly reduce intestinal injury. This finding indicates that inhibiting Cx43 regulates the transfer of miR-181b between adjacent cells, thereby reducing the activity of the Sirt1/FOXO3a signalling pathway and reducing the degree of intestinal injury during sepsis. CONCLUSIONS: In sepsis, the enhancement of Cx43 gap junctions leads to an increase in miR-181b intercellular transfer, affects the downstream SIRT1/FOXO3a signalling pathway and causes cell and tissue damage.

Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis.

Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A-GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A-GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A-GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.

DIAPH3 is a prognostic biomarker and inhibit colorectal cancer progression through maintaining EGFR degradation.

BACKGROUND: Actin cytoskeleton is connected with the processes of cell proliferation and migration in colorectal cancer (CRC). However, it is unknown how to accomplish these adjustments in CRC by actin cytoskeleton genes (ACGs) and here we investigated the role of hub prognosis-related ACGs-Diaphanous-related formin 3 (DIAPH3) in CRC, as a potential, novel target. METHODS: The ACGs gene set from the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to group CRC patients and select prognosis-related ACGs by univariate and multivariate Cox regression for constructing prognostic model. Next, we tested hub prognosis-related ACGs- DIAPH3 expression in CRC and clarified the role of DIAPH3 by shRNA constructs in KM12 and SW480. Activation of EGFR was analyzed by western blot and immunofluorescence. RESULTS: The results showed that actin cytoskeleton function is a significant prognostic factor for CRC patients and related to clinicopathological characteristics such as T stage and lymph node metastasis. A prognostic model constructed by four prognosis-related ACGs has a moderate intensity to 1-year Survival (AUC = 0.71). And hub prognosis-related ACGs DIAPH3 is downregulated in CRC. Knockdown of DIAPH3 could promote the proliferation and migration capacity of CRC. In addition, DIAPH3-silenced cells increase EGFR phosphorylation by inhibiting EGFR transportation to lysosome. CONCLUSIONS: ACGs play a significant role in tumor invasion and have the potential to predict the prognosis of CRC. Prognosis-related ACGs DIAPH3 might be a new prognostic biomarker and DIAPH3 could inhibit CRC progression through maintaining EGFR degradation.

PRRX1 promotes colorectal cancer stemness and chemoresistance via the JAK2/STAT3 axis by targeting IL-6.

Background: Stemness acquirement is one of the hallmarks of cancer and the major reason for the chemoresistance and poor prognosis of colorectal cancer (CRC). Previous research has revealed the stimulatory role of paired related homeobox 1 (PRRX1) on CRC metastasis. However, the role of PRRX1 in stemness acquirement and chemoresistance of CRC is still not clear. Methods: A retrospective cohort study was performed to investigate the relationship between PRRX1 expression and multiple clinicopathological characteristics of CRC patients. The functional effects of PRRX1 on stemness and chemoresistance of CRC cells were validated by in vitro and in vivo assays. Gene set enrichment analysis (GSEA) and JASPAR software were performed to predict the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), Western blot, immunofluorescence, and dual-luciferase reporter assays were used to confirm the PRRX1-mediated signaling and its downstream factors. Results: The expression of PRRX1 was up-regulated in CRC tissues and cell lines compared to normal epithelial tissues and cell lines. High expression of PRRX1 was tightly associated with the metastasis, chemoresistance, and poor prognosis of CRC patients. Additionally, PRRX1 significantly promoted the proliferation, viability, stemness, and chemoresistance of CRC cells, as well as the activation of the interleukin-6 (IL-6)/JAK2/STAT3 axis. Inhibiting the expression of IL-6 dramatically eliminated the effects of PRRX1 on CRC cell stemness and chemoresistance. Conclusions: PRRX1 plays a vital role in the stemness and chemoresistance of CRC cells via JAK2/STAT3 signaling by targeting IL-6. Further, PRRX1 may be a valid biomarker for predicting the effect of chemotherapy and prognosis of CRC patients.

A new side-effect of sufentanil: increased monocyte-endothelial adhesion.

BACKGROUND: Opioids have been identified by the World Health Organization to be 'indispensable for the relief of pain and suffering'. Side-effects, such as nausea, vomiting, postoperative delirium, and effects on breathing, of opioids have been well investigated; however, the influence of opioids on monocyte-endothelial adherence has never been reported. Therefore, we explored the effects of representative opioids, fentanyl, sufentanil, and remifentanil, on monocyte-endothelial adherence and the underlying mechanisms. METHODS: We built a cell adhesion model with U937 monocytes and human umbilical vein endothelial cells (HUVECs). Two kinds of connexin43 (Cx43) channel inhibitors, 18-α-GA and Gap 27, were used to alter Cx43 channel function in U937 monocytes and HUVECs, respectively, to determine the effects of Cx43 channels on U937-HUVEC adhesion. Subsequently, the effects of fentanyl, sufentanil and remifentanil on Cx43 channel function and U937-HUVEC adhesion were explored. RESULTS: When fentanyl, sufentanil and remifentanil acted on monocytes or endothelial cells, their effects on monocyte-endothelial adherence differed. When acting on U937 monocytes, sufentanil significantly increased U937-HUVEC adhesion which was associated with reduced release of ATP from Cx43 channels, while fentanyl and remifentanil did not have these influences. Although sufentanil could also inhibit Cx43 channel function in HUVECs, it had no effect on ATP release from HUVECs or U937-HUVECs adhesion. CONCLUSIONS: We demonstrated that sufentanil application increases monocyte-endothelial adherence which was associated with reduced release of ATP from Cx43 channels in monocytes. This side-effect of sufentanil should be considered seriously by clinicians.

BMP3 suppresses colon tumorigenesis via ActRIIB/SMAD2-dependent and TAK1/JNK signaling pathways.

BACKGROUND: BMP3 gene is often found hypermethylated and hence inactivated in several types of cancers including colorectal cancer (CRC), indicating that it has a suppressor role in carcinogenesis. Though BMP3 is a reliable biomarker for screening CRC, the molecular mechanism of BMP3 in carcinogenesis remains largely unknown. METHODS: The expression level of BMP3 was examined by immunohistochemistry staining and western blot. Methylation-specific PCR (MSP) and real-time quantitative MSP were used to test the hypermethylation status of BMP3 gene. Analyses of BMP3 function in colon cancer cell proliferation, migration, invasion, and apoptosis were performed using HCT116 and KM12 cells. BMP3 was further knocked down or overexpressed in CRC cells, and the effects on cell growth of xenograft tumors in nude mice were assessed. Co-immunoprecipitation and immunofluorescence staining were used to analyze the association between BMP3 and BMPR2 or BMP3 and ActRIIB. Microarray analysis was performed to identify most differentially expressed genes and pathways regulated by BMP3. The BMP3-regulated SMAD2-dependent signaling pathway and TAK1/JNK signal axes were further investigated by quantitative PCR and western blot. RESULTS: BMP3 gene was hypermethylated and its expression was downregulated in both CRC tissues and cell lines. Expressing exogenous BMP3 in HCT116 inhibited cell growth, migration, and invasion and increased rate of apoptosis both in vitro and in vivo. However, shRNA-mediated attenuation of endogenous BMP3 in KM12 reversed such inhibitory and apoptotic effects. Furthermore, BMP3 could bind to ActRIIB, an activin type II receptor at the cellular membrane, thereby activating SMAD2-dependent pathway and TAK1/JNK signal axes to regulate downstream targets including caspase-7, p21, and SMAD4 that play crucial roles in cell cycle control and apoptosis. CONCLUSIONS: Our study reveals a previously unknown mechanism of BMP3 tumor suppression in CRC and provides a rationale for future investigation of BMP3 as a potential target for the development of novel therapeutic agents to fight CRC.

Cx43 Inhibition Attenuates Sepsis-Induced Intestinal Injury via Downregulating ROS Transfer and the Activation of the JNK1/Sirt1/FoxO3a Signaling Pathway.

Intestinal injury has long been considered to play a crucial role in the pathophysiology of sepsis and has even been characterized as the "motor" of it. Thus, we explored the effects of connexin43 (Cx43) on sepsis-induced intestinal injury in order to provide potential therapeutic strategies. Rat cecal ligation and puncture (CLP) models in vivo and cell models (IEC-6 cells) pretreated with LPS in vitro were used in the current study. Firstly, different methods, such as Cx43 inhibitors (18-α-GA and oleamide) or siRNA targeting Cx43 and N-acetyl cysteine (NAC) (a kind of ROS scavenger), were used to observe the effects of Cx43 channels mediating ROS transfer on intestinal injury. Secondly, the influence of ROS content on the activity of the JNK1/Sirt1/FoxO3a signaling pathway was explored through the application of NAC, sp600125 (a JNK1 inhibitor), and nicotinamide (a Sirt1 inhibitor). Finally, luciferase assays and ChIP were used to determine the direct regulation of FoxO3a on proapoptotic proteins, Bim and Puma. The results showed that sepsis-induced intestinal injury presented a dynamic change, coincident with the alternation of Cx43 expression. The inhibition of Cx43 attenuated CLP-induced intestinal injury in vivo and LPS-induced IEC-6 injury in vitro. The changes of Cx43 channel function regulated ROS transfer between the neighboring cells, which mediated the activation of the JNK1/Sirt1/FoxO3a signaling pathway. FoxO3a directly affected its downstream target genes, Bim and Puma, which are responsible for cell or tissue apoptosis. In summary, our results suggest that Cx43 inhibition suppresses ROS transfer and inactivates the JNK1/Sirt1/FoxO3a signaling pathway to protect against sepsis-induced intestinal injury.

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway.

BACKGROUND/AIMS: The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. METHODS: The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial-mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. RESULTS: XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. CONCLUSION: High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells.

Overexpression of Rictor protein in colorectal cancer is correlated with tumor progression and prognosis.

In order to understand the clinical significance of rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) in colorectal cancer (CRC), 62 CRC tissue samples excised during operations were evaluated by immunohistochemistry. Analysis of the association between the expression level of Rictor protein and clinicopathological parameters demonstrated that the expression level of Rictor in CRC tissues was significantly higher than that in paracarcinoma tissues (P<0.0001). In cellular experiments, this result was further confirmed by comparing differences in Rictor expression between the CRC cell lines HCT116, SW480 and LoVo, and the human normal liver cell line HL-7702. It was also noticed that the expression of Rictor was associated with Dukes stage, lymphatic metastasis and prognosis, as determined by χ2 test, Kaplan-Meier analysis and log-rank test. These results suggest that Rictor may be a novel target for the treatment and prognostic assessment of CRC patients in the future.

Gap junction composed of connexin43 modulates 5­fluorouracil, oxaliplatin and irinotecan resistance on colorectal cancers.

Chemotherapy is one of the most commonly used therapeutic strategies for metastatic colon cancer. However, the development of resistance to chemotherapeutic agents limits their application in clinical use. The underlying mechanisms of this resistance development require further elucidation. The current study investigated the effects of connexin43 (Cx43) gap junctions on 5­fluorouracil (5­FU), oxaliplatin and irinotecan in colon cancer cells. Three different methods were used to manipulate Cx43 gap junction function: i) Cell culture at different densities; ii) pretreatment with a Cx43 specific inhibitor or enhancer; and iii) Cx43 gene knock­down. Results indicated that the cell toxicity of 5­FU, oxaliplatin and irinotecan was cell density­dependent, which was mediated by gap junctions. Downregulation of Cx43 gap junction functioning attenuated 5­FU, oxaliplatin and irinotecan toxicity in colon cancer cells, which was increased in cells treated with a Cx43 gap junction function enhancer. Thus, the results of the present study suggest that resistance to 5­FU, oxaliplatin and irinotecan in colon cancer cells was relative to Cx43 expression loss as cancer developed, which may indicate a novel basis for therapeutic strategy development to combat drug resistance in numerous cell types, in addition to colon cancer cells.

[Expression of Rictor and mTOR in colorectal cancer and their clinical significance].

OBJECTIVE: To explore the expression of Rictor and mTOR in the colorectal cancer and their clinical significance. METHODS: The expression levels of Rictor and mTOR in HCT116, SW480, LoVo and HCoEpiC cells were detected by indirect immunofluorescence and Western blotting. Sixty-two paraffin-embedded surgical specimens of colorectal cancer tissue and adjacent tissues were examined for Rictor expression using immunohistochemistry. The association of the expression levels of Rictor protein with the clinicopathologic features and the overall survival of the patients was analyzed. RESULTS: The expression level of Rictor was significantly higher in colorectal cancer tissues than in the adjacent tissues (P<0.05). The expression levels of Rictor and mTOR in the colon cancer cell lines were higher than those in human normal colon epithelial cell line HCoEpiC. The expression of Rictor was correlated with Dukes stage and lymphatic metastasis of the tumors but not with other clinicopathological parameter (P>0.05). Patients with Rictor expression had a lower overall survival rate than those without Rictor expression. CONCLUSION: Rictor overexpression is associated with the carcinogenesis and progression of colorectal cancer and can be an independent indicator for evaluating the prognosis of colorectal cancer patients.

Epigenetic silencing of miR-490-3p promotes development of an aggressive colorectal cancer phenotype through activation of the Wnt/ß-catenin signaling pathway.

The Wnt/ß-catenin pathway is known to contribute to colorectal cancer (CRC) progression, although little is known about the contribution of ß-catenin on this process. We investigated the role of miR-490-3p, which was recently reported to suppress tumorigenesis through its effect on Wnt/ß-catenin signaling. We found that hypermethylation of the miR-490-3p promoter down-regulates miR-490-3p expression in CRC tissue. Gain- and loss-of-function assays in vitro and in vivo reveal that miR-490-3p suppresses cancer cell proliferation by inducing apoptosis and inhibits cell invasiveness by repressing the initiation of epithelial-to-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. The frequently rearranged in advanced T-cell lymphomas (FRAT1) protein was identified as a direct target of miR-490-3p and contributes to its tumor-suppressing effects. miR-490-3p appears to have an inhibitory effect on ß-catenin expression in nuclear fractions of CRC cells, whereas FRAT1 expression is associated with the accumulation of ß-catenin in the nucleus of cells, which could be weakened by transfection with miR-490-3p. Our findings suggest that the miR-490-3p/FRAT1/ß-catenin axis is important in CRC progression and provides new insight into the molecular mechanisms underlying CRC. They may help to confirm the pathway driving CRC aggressiveness and serve for the development of a novel miRNA-targeting anticancer therapy.

[A comparative study of three-dimensional versus two-dimensional laparoscopic subtotal thyroidectomy via a breast approach].

OBJECTIVE: To explore the safety, efficacy and feasibility of 3D laparoscopic subtotal thyroidectomy via a breast approach. METHODS: The clinical data of 30 patients undergoing 3D laparoscopic subtotal thyroidectomy via a breast approach were analyzed in comparison with 30 patients receiving traditional laparoscopic subtotal thyroidectomy during the period from September, 2013 to December, 2013. The operation time, blood loss, postoperative drainage, postoperative hospital stay, and total hospitalization expenses were compared between the two groups. RESULTS: The operation time in the 3D group was significantly shorter than that in the 2D group (45∓26.3 vs 62∓24.8 min, t=0.53, P<0.05). The intraoperative blood loss, postoperative drainage, postoperative hospital stay and total hospitalization expenses did not show significant differences between the two groups. CONCLUSIONS: 3D laparoscopic subtotal thyroidectomy via a breast approach is safe and effective and shortens the operation time, and can be used as a routine operation for subtotal thyroidectomy.

[Research progress of three-dimensional laparoscope system].

The lack of depth perception and spatial orientation in two-dimensional image of traditional laparoscopy require long-term training of the surgeons. Three-dimensional (3D) laparoscopy provides stereoscopic visions as compared to monocular views in a traditional laparoscopic system. In this review, the authors summarize the clinical application of 3D laparoscopy and its current research progress.