ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis.

The resistance to anoikis plays a critical role in the metastatic progression of various types of malignancies, including gastric cancer (GC). Nevertheless, the precise mechanism behind anoikis resistance is not fully understood. Here, our primary focus was to examine the function and underlying molecular mechanism of Integrin beta-like 1 (ITGBL1) in the modulation of anoikis resistance and metastasis in GC. The findings of our investigation have demonstrated that the overexpression of ITGBL1 significantly augmented the resistance of GC cells to anoikis and promoted their metastatic potential, while knockdown of ITGBL1 had a suppressive effect on both cellular processes in vitro and in vivo. Mechanistically, we proved that ITGBL1 has a role in enhancing the resistance of GC cells to anoikis and promoting metastasis through the AKT/Fibulin-2 (FBLN2) axis. The inhibition of AKT/FBLN2 signalling was able to reverse the impact of ITGBL1 on the resistance of GC cells to anoikis and their metastatic capability. Moreover, the expression levels of ITGBL1 were found to be significantly elevated in the cancerous tissues of patients diagnosed with GC, and there was a strong correlation observed between high expression levels of ITGBL1 and worse prognosis among individuals diagnosed with GC. Significantly, it was revealed that within our cohort of GC patients, individuals exhibiting elevated ITGBL1 expression and diminished FBLN2 expression experienced the worst prognosis. In conclusion, the findings of our study indicate that ITGBL1 may serve as a possible modulator of resistance to anoikis and the metastatic process in GC.

B7H3 increases ferroptosis resistance by inhibiting cholesterol metabolism in colorectal cancer.

Ferroptosis, a newly discovered form of regulated cell death, has been reported to be associated with multiple cancers, including colorectal cancer (CRC). However, the underlying molecular mechanism is still unclear. In this study, we identified B7H3 as a potential regulator of ferroptosis resistance in CRC. B7H3 knockdown decreased but B7H3 overexpression increased the ferroptosis resistance of CRC cells, as evidenced by the expression of ferroptosis-associated genes (PTGS2, FTL, FTH, and GPX4) and the levels of important indicators of ferroptosis (malondialdehyde, iron load). Moreover, B7H3 promoted ferroptosis resistance by regulating sterol regulatory element binding protein 2 (SREBP2)-mediated cholesterol metabolism. Both exogenous cholesterol supplementation and treatment with the SREBP2 inhibitor betulin reversed the effect of B7H3 on ferroptosis in CRC cells. Furthermore, we verified that B7H3 downregulated SREBP2 expression by activating the AKT pathway. Additionally, multiplex immunohistochemistry was carried out to show the expression of B7H3, prostaglandin-endoperoxide synthase 2, and SREBP2 in CRC tumor tissues, which was associated with the prognosis of patients with CRC. In summary, our findings reveal a role for B7H3 in regulating ferroptosis by controlling cholesterol metabolism in CRC.

SLC6A14 facilitates epithelial cell ferroptosis via the C/EBPß-PAK6 axis in ulcerative colitis.

Emerging evidence suggests that ferroptosis is involved in the pathogenesis of ulcerative colitis (UC). However, the key regulator of this process remains uncertain. In this study, we aimed to explore the roles of solute carrier (SLC) family 6 member 14 (SLC6A14) in regulating ferroptosis in UC. The expression of SLC6A14 was significantly increased and positively associated with that of prostaglandin-endoperoxide synthase 2 (PTGS2) in tissue samples from patients with UC. Moreover, a series of in vitro and in vivo experiments showed that SLC6A14 knockdown markedly suppressed ferroptosis. RNA sequencing revealed that SLC6A14 inhibited the expression of P21 (RAC1)-activated kinase 6 (PAK6) and that PAK6 knockdown abolished the effects of SLC6A14 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in Caco-2 cells. Furthermore, chromatin immunoprecipitation (ChIP) and Western blot analysis demonstrated that SLC6A14 negatively regulated PAK6 expression in a CCAAT enhancer binding protein beta (C/EBPß)-dependent manner. Collectively, these findings indicate that SLC6A14 facilitates ferroptosis in UC by promoting C/EBPß expression and binding activity to inhibit PAK6 expression, suggesting that targeting SLC6A14-C/EBPß-PAK6 axis-mediated ferroptosis may be a promising therapeutic alternative for UC.

Analysis of Endoscopy Intervention in Postesophagectomy Anastomotic Leak: A Retrospective Study.

BACKGROUND: Anastomotic leak after esophagectomy is one of the most challenging complications resulting in a high morbidity and mortality and prolonged hospitalization. The aim of this retrospective study was to access the impact of endoscopy intervention in anastomotic leak. METHODS: A retrospective review was conducted at our hospital from January 2008 to December 2016. In total, 263 patients who were diagnosed with an anastomotic leak after esophagectomy and underwent endoscopy examination were included in this study. First, all patients were divided into two groups based on a single criteria-whether they received endoscopy intervention or not-and comparisons were conducted between the two groups. Second, we categorized all patients into three groups based on the diameter of the anastomotic leak (group I: <5 mm; group II: 5-15 mm; group III: >15 mm). Detailed analyses were made for each group. Factors we considered included demographic factors, the length of postoperative hospital stay, the amount of medical expenditure, limited days of oral intake, and the incurrence of complications. Data relating to those factors were collected and then analyzed using standard statistic tools. RESULTS: In general, the difference between endoscopy intervention and conservative measure was significant. Moreover, the hospital stay (p < 0.001; p = 0.018), medical expenditure (p < 0.001; p = 0.003), limited days of oral intake (p < 0.001; p = 0.019), and postoperative complications such as hemorrhage (p < 0.001; p = 0.036), tracheoesophageal fistula (p = 0.002; p = 0.017), and anastomosis stricture (p = 0.03; p = 0.026) were significantly lower among patients who received endoscopy intervention in groups II and III. However, no significant difference was identified between endoscopy intervention and conservative measure in group I. CONCLUSIONS: Endoscopy intervention is safe and effective in the diagnosis and treatment of postesophagectomy anastomotic leak. Especially for patients with a diameter of anastomotic leaks greater than 5 mm, the advantages of endoscopy intervention should not be neglected.

High frequency of mononuclear myeloid-derived suppressor cells is associated with exacerbation of inflammatory bowel disease.

Exacerbation and relapse of inflammatory bowel disease (IBD) is associated with reduced antibacterial immunity and increased immune regulatory activity, but the source of increased immune regulation during episodes of disease activity is unclear. Myeloid-derived suppressor cells (MDSCs) are a cell type with a well-recognized role in limiting immune reactions. MDSC function in IBD and its relation to disease activity, however, remains unexplored. Here we show that patients with either ulcerative colitis (UC) or Crohn's disease (CD) have high peripheral blood levels of mononuclear MDSCs. Especially exacerbation of disease is associated with higher levels of mononuclear MDSC counts compared with those in remission of disease. Interestingly, chronic experimental colitis in mice coincides with increased MDCS mobilization. Thus, our results suggest that mononuclear MDCS are endogenous antagonists of immune system functionality in mucosal inflammation and the depression of antibacterial immunity associated with exacerbation of disease might involve increased activity of the MDSC compartment.

B7-H3 regulates anti-tumor immunity and promotes tumor development in colorectal cancer.

Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract and one of the most common causes of cancer-related deaths worldwide. Immune checkpoint inhibitors have become a milestone in many cancer treatments with significant curative effects. However, its therapeutic effect on colorectal cancer is still limited. B7-H3 is a novel immune checkpoint molecule of the B7/CD28 family and is overexpressed in a variety of solid tumors including colorectal cancer. B7-H3 was considered as a costimulatory molecule that promotes anti-tumor immunity. However, more and more studies support that B7-H3 is a co-inhibitory molecule and plays an important immunosuppressive role in colorectal cancer. Meanwhile, B7-H3 promoted metabolic reprogramming, invasion and metastasis, and chemoresistance in colorectal cancer. Therapies targeting B7-H3, including monoclonal antibodies, antibody drug conjugations, and chimeric antigen receptor T cells, have great potential to improve the prognosis of colorectal cancer patients.

[The expression of peripheral Th1 and Th17 cells in inflammatory bowel disease and its potential clinical value].

OBJECTIVE: To explore the probable role of Th1 and Th17 cells in the pathogenesis of inflammatory bowel disease (IBD). METHODS: The peripheral blood mononuclear cells (PBMCs) from peripheral blood specimens were collected in the study, including 40 healthy controls, 42 ulcerative colitis (UC) and 39 Crohn's disease (CD). The proportion of Th1 and Th17 cells in the PBMCs was detected with flow cytometry after stimulated by PMA and ionomycin. The result and the clinical data were analyzed. RESULT: The Th1 cell expression was increased in CD (38.32 ± 16.18)% and UC group (34.23 ± 11.60)%, compared with the controls (24.58 ± 10.02)% (P < 0.01). During the convalescence, the Th1 expression in the CD and UC groups in vivo was significantly reduced without difference between the two groups (P > 0.05) . In the IBD group , significant difference in the frequency of Th17 cells could be found between the CD group (2.51 ± 1.59)% and the UC group (4.15 ± 2.75)%, while the Th17 cells were increased in both groups, compared with the controls (1.44 ± 0.73)% (P < 0.05) . Obvious difference in the frequency of Th17 cells could be found between patients at different activity stages and remission stages. The proportion of Th17 cells were higher in the UC patients than that in the CD patients (P < 0.01) . The Th17/Th1 ratio of CD patients, UC patients were 0.08 ± 0.06, 0.14 ± 0.11, which were both higher that in the controls (0.07 ± 0.06). Significant difference could be found between the UC group and the CD group (P < 0.01). CONCLUSIONS: The higher proportion of Th1 and Th17 cells are detected in the peripheral blood of IBD patients, which is correlated closely to the activity of the disease. Th1 and Th17 cells may play an important role in the pathogenesis of IBD.

Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers.

Pancreatic cancer is one of the common malignant tumors of the digestive system and is known as the "king of cancers". It is extremely difficult to diagnose at an early stage, the disease progresses rapidly, and the effect of chemotherapy and radiotherapy is poor, so the prognosis of pancreatic cancer patients is very poor. Numerous studies have suggested that hypoxia is closely related to the development and progression of pancreatic cancer. Inadequate blood supply and desmoplasia in the microenvironment of pancreatic cancer can result in its extreme hypoxia. This hypoxic microenvironment can further contribute to angiogenesis and desmoplasia. Hypoxia is mediated by the complex hypoxia inducible factor (HIF) signaling pathway and plays an important role in the formation of a highly immunosuppressive microenvironment and the metastasis of pancreatic cancer. Further work on the hypoxic microenvironment will help clarify the specific mechanisms of the role of hypoxia in pancreatic cancer and provide a basis for the realization of hypoxia-targeted therapeutic and diagnostic strategies.

Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease.

Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 µg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 µg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95 µg/mL, p = .03). The HLA-DQA1*05 rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.

B7-H3 confers stemness characteristics to gastric cancer cells by promoting glutathione metabolism through AKT/pAKT/Nrf2 pathway.

BACKGROUND: Cancer stem-like cells (CSCs) are a small subset of cells in tumors that exhibit self-renewal and differentiation properties. CSCs play a vital role in tumor formation, progression, relapse, and therapeutic resistance. B7-H3, an immunoregulatory protein, has many protumor functions. However, little is known about the mechanism underlying the role of B7-H3 in regulating gastric cancer (GC) stemness. Our study aimed to explore the impacts of B7-H3 on GC stemness and its underlying mechanism. METHODS: GC stemness influenced by B7-H3 was detected both in vitro and in vivo . The expression of stemness-related markers was examined by reverse transcription quantitative polymerase chain reaction, Western blotting, and flow cytometry. Sphere formation assay was used to detect the sphere-forming ability. The underlying regulatory mechanism of B7-H3 on the stemness of GC was investigated by mass spectrometry and subsequent validation experiments. The signaling pathway (Protein kinase B [Akt]/Nuclear factor erythroid 2-related factor 2 [Nrf2] pathway) of B7-H3 on the regulation of glutathione (GSH) metabolism was examined by Western blotting assay. Multi-color immunohistochemistry (mIHC) was used to detect the expression of B7-H3, cluster of differentiation 44 (CD44), and Nrf2 on human GC tissues. Student's t -test was used to compare the difference between two groups. Pearson correlation analysis was used to analyze the relationship between two molecules. The Kaplan-Meier method was used for survival analysis. RESULTS: B7-H3 knockdown suppressed the stemness of GC cells both in vitro and in vivo . Mass spectrometric analysis showed the downregulation of GSH metabolism in short hairpin B7-H3 GC cells, which was further confirmed by the experimental results. Meanwhile, stemness characteristics in B7-H3 overexpressing cells were suppressed after the inhibition of GSH metabolism. Furthermore, Western blotting suggested that B7-H3-induced activation of GSH metabolism occurred through the AKT/Nrf2 pathway, and inhibition of AKT signaling pathway could suppress not only GSH metabolism but also GC stemness. mIHC showed that B7-H3 was highly expressed in GC tissues and was positively correlated with the expression of CD44 and Nrf2. Importantly, GC patients with high expression of B7-H3, CD44, and Nrf2 had worse prognosis ( P = 0.02). CONCLUSIONS: B7-H3 has a regulatory effect on GC stemness and the regulatory effect is achieved through the AKT/Nrf2/GSH pathway. Inhibiting B7-H3 expression may be a new therapeutic strategy against GC.

HES1 promotes aerobic glycolysis and cancer progression of colorectal cancer via IGF2BP2-mediated GLUT1 m6A modification.

Aerobic glycolysis has been shown to play a key role in tumor cell proliferation and metastasis. However, how it is directly regulated is largely unknown. Here, we found that HES1 expression was significantly higher in CRC tissues than that in adjacent normal tissues. Moreover, high HES1 expression is associated with poor survival in CRC patients. HES1 knockdown markedly inhibited cell growth and metastasis both in vitro and in vivo. Additionally, silencing of HES1 suppressed aerobic glycolysis of CRC cells. Mechanistic studies revealed that HES1 knockdown decreased the expression of GLUT1, a key gene of aerobic glycolysis, in CRC cells. GLUT1 overexpression abolished the effects of HES1 knockdown on cell aerobic glycolysis, proliferation, migration and invasion. ChIP-PCR and dual-luciferase reporter gene assay showed that HES1 directly bound the promoter of IGF2BP2 and promoted IGF2BP2 expression. Furthermore, our data indicated that IGF2BP2 recognized and bound the m6A site in the GLUT1 mRNA and enhanced its stability. Taken together, our findings suggest that HES1 has a significant promotion effect on CRC aerobic glycolysis and progression by enhancing the stability of m6A-modified GLUT1 mRNA in an IGF2BP2-dependent manner, which may become a viable therapeutic target for the treatment of CRC in humans. The mechanism of HES1 regulating glycolysis in CRC.

Circular RNA circLDLR facilitates cancer progression by altering the miR-30a-3p/SOAT1 axis in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been reported to play critical regulatory roles in tumorigenesis, serving as tumor biomarkers and therapeutic targets. However, the contributions of circRNAs to CRC tumorigenesis are unclear. In our study, high expression of circLDLR was found in CRC tissues and cells and was closely associated with the malignant progression and poor prognosis of CRC patients. We demonstrated that circLDLR boosts growth and metastasis of CRC cells in vitro and in vivo, and modulates cholesterol levels in vitro. Mechanistically, we showed that circLDLR competitively binds to miR-30a-3p and prevents it from reducing the SOAT1 level, facilitating the malignant progression of CRC. In sum, our findings illustrate that circLDLR participates in CRC tumorigenesis and metastasis via the miR-30a-3p/SOAT1 axis, serving as a potential biomarker and therapeutic target in CRC.

Astragalus polysaccharide prevents ferroptosis in a murine model of experimental colitis and human Caco-2 cells via inhibiting NRF2/HO-1 pathway.

Ulcerative colitis (UC) is a relapsing and remitting inflammatory bowel disease (IBD), but current conventional drugs lack efficacy. Astragalus polysaccharide (APS) is an active ingredient of Astragalus membranaceus and has been shown to ameliorate experimental colitis. In the present study, we aimed to investigate how APS affects the ferroptosis of intestinal epithelial cells in dextran sulfate sodium (DSS)-induced experimental colitis in mice. Our data showed that APS administration attenuated total weight loss, colon length shortening, disease activity index (DAI) scores, histological damage, and the expression of inflammatory cytokines in the colon of DSS-challenged mice. Moreover, we observed that treatment with APS obviously inhibited ferroptosis in both DSS-challenged mice and RSL3-stimulated Caco-2 cells, as indicated by the decrease in the expression of ferroptosis-associated genes (PTGS2, FTH, and FTL) and the levels of surrogate ferroptosis markers (MDA, GSH, and iron load). Mechanistically, the inhibitory effects of APS on ferroptosis in DSS-challenged mice and RSL3-stimulated Caco-2 cells were associated with the NRF2/HO-1 pathway. Collectively, our findings identify a new role of APS in preventing ferroptosis in a murine model of experimental colitis and human Caco-2 cells via inhibiting NRF2/HO-1 pathway.

Jejunal hemolymphangioma: A case report.

RATIONALE: Hemolymphangioma is a benign tumor comprised of the newly-formed lymph spaces and blood vessels, which can usually be found in the head and neck of the affected children. There are few reports regarding cases with hemolymphangioma in small intestine, spleen, esophagus, and other organs. PATIENT CONCERNS: Herein, a 55-year-old woman was presented in this study, she had complained of discomfort in the right upper abdomen for 2 months, and was discovered with a space-occupying lesion in proximal jejunum on computed tomography (CT). Eventually, the lesions were confirmed through double-balloon enteroscopy (DBE) to be located in the jejunum 60 cm away from the Treitz ligament. DIAGNOSE: Subsequently, the small intestine was partially resected, and postoperative pathology had confirmed the diagnosis of small intestinal hemolymphangioma. INTERVENTIONS: Excisional surgery of the lesion was planned. On surgery, the lesions were discovered to be about 33 cm to 22 cm when engorged the superficial vessels. No enlarged lymph nodes were seen at the root of the mesentery, and no obvious lesion was observed in the remaining small intestine. OUTCOMES: Follow-up for 6 months showed no recurrence. LESSONS: Hemolymphangioma lacks typical clinical symptoms, and the correct preoperative diagnosis of hemolymphangioma remains challenging. Due to the increasing use of endoscopic diagnostic techniques, it is expected that hemolymphangioma in gastrointestinal tract may be detected and endoluminal located before surgery more feasibly. This case report aimed to highlight the contributions of CT and DBE to an accurate preoperative diagnosis and surgical strategy planning.