Cryptogenic Multifocal Ulcerating Stenosing Enteropathy: A Rare Case of Small Bowel Stenosis.

BACKGROUND Cryptogenic multifocal ulcerating stenosing enteropathy (CMUSE) is a rare noninfectious chronic inflammatory disease of the digestive tract confined to the small bowel. Chronic inflammatory wasting leads to protein loss and weight reduction, and some patients eventually develop small bowel stenosis. The etiopathogenesis of CMUSE remains unknown. CASE REPORT A thin 62-year-old man was admitted to the hospital with abdominal pain and distension accompanied by bilateral lower-extremity edema for 2 months. After a series of medical tests, rheumatic or immune-related diseases, hyperthyroidism, and tuberculosis were excluded, and common digestive system diseases were also excluded. Abdominal CT showed incomplete obstruction of the small bowel. Enteroscopy showed small-bowel luminal narrowing. The patient subsequently underwent partial resection of the small bowel with end-to-side anastomosis. The small-bowel stricture was about 120 cm from the ileocecal junction, and about 12 cm of small bowel was resected. Postoperative pathology of the resected material revealed multifocal ulceration of the mucosa with massive inflammatory cell infiltration and extensive hyperplastic fibrous tissue, consistent with the characteristics of CMUSE disease. At follow-up 6 months after surgery, he had no abdominal pain or distension, and his anemia and lower-extremity edema were improved. CONCLUSIONS CMUSE diagnosis requires a combination of patient history, imaging, endoscopy, pathology, and exclusion of other digestive disorders, such as Crohn's disease. It is a chronic wasting disease, often accompanied by weight loss, abdominal pain, melena, and hypoproteinemia. Surgery is an important treatment for intestinal strictures caused by CMUSE.

Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis.

HMGA2, a pivotal transcription factor, functions as a versatile regulator implicated in the progression of diverse aggressive malignancies. In this study, mass spectrometry was employed to identify ubiquitin-specific proteases that potentially interact with HMGA2, and USP48 was identified as a deubiquitinating enzyme of HMGA2. The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation, while the deprivation of USP48 promoted HMGA2 degradation, thereby suppressing tumor invasion and metastasis. We discovered that USP48 undergoes SUMOylation at lysine 258, which enhances its binding affinity to HMGA2. Through subsequent phenotypic screening of small molecules, we identified DUB-IN-2 as a remarkably potent pharmacological inhibitor of USP48. Interestingly, the small-molecule inhibitor targeting USP48 induces destabilization of HMGA2. Clinically, upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer (CRC). Collectively, our study not only elucidates the regulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC, but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.

Case Report of Overlapping Pyloric Obstruction Due to Dichlorvos Poisoning and Cholelithiasis with Choledocholithiasis.

BACKGROUND Pyloric obstruction after dichlorvos poisoning causes repeated vomiting and inability to eat. Choledocholithiasis and cholelithiasis are the common digestive diseases, with high morbidity and relapse in elderly patients. However, the complex situation of these diseases' coexistence is a clinically intractable problem, and literature on selecting optimal surgical planning is scarce. CASE REPORT A thin 79-year-old woman took dichlorvos due to family conflicts. She improved after being urgently sent to local hospital for gastric lavage and detoxification. Over the next 3 months, she presented with intermittent nausea, vomiting, epigastric pain, and mental apathy, and was readmitted. Gastroscopy showed extensive scarring in the antrum, pyloric obstruction, and gastric retention. Magnetic resonance cholangiopancreatography revealed gallstones and choledocholithiasis. Also, she presented with gastric retention, hypertension, moderate anemia, hypoproteinemia, and electrolyte disturbances. After hospitalization, conservative treatment was performed, without improving vomiting, followed by surgical treatment. Gastrojejunostomy, Braun anastomosis, and nasojejunal feeding tube placement were performed for pyloric stenosis; cholecystectomy for cholelithiasis; and choledochotomy, intraoperative choledochoscopy examination, basket stone extraction, and primary suture of common bile duct without indwelling T tube for choledocholithiasis. Patient recovered and was discharged 9 days after surgery. She was recovered well, without vomiting, at 2-month follow-up. CONCLUSIONS Gastrojejunostomy plus Braun anastomosis is effective treatment of elderly patients with pyloric obstruction formed after pesticide-induced corrosion. Careful selection of choledocholithotomy with primary suture without indwelling T tube reduced postoperative pain and accelerated recovery. This complex case of pyloric obstruction with gallbladder and bile duct stones provides useful considerations for clinical treatment.

UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma.

Interferon (IFN) exerts its effects through interferon-stimulated genes (ISGs), but its efficacy is limited by interferon resistance, which can be caused by the ubiquitination of key proteins. UBE2O was initially identified as a promising therapeutic target based on data from the TCGA and iUUCD 2.0 databases. Through the inhibition of UBE2O, interferon α/ß signaling and overall interferon signaling were activated. Integrating data from proteomic, mass spectrometry, and survival analyses led to the identification of IFIT3, a mediator of interferon signaling, as a ubiquitination substrate of UBE2O. The results of in vitro and in vivo experiments demonstrated that the knockdown of UBE2O can enhance the efficacy of interferon-α by upregulating IFIT3 expression. K236 was identified as a ubiquitination site in IFIT3, and the results of rescue experiments confirmed that the effect of UBE2O on interferon-α sensitivity is dependent on IFIT3 activity. ATO treatment inhibited UBE2O and increased IFIT3 expression, thereby increasing the effectiveness of interferon-α. In conclusion, these findings suggest that UBE2O worsens the therapeutic effect of interferon-α by targeting IFIT3 for ubiquitination and degradation.

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation.

BACKGROUND: Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. METHODS: The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). RESULTS: Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. CONCLUSIONS: Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.

Many metabolism-related genes undergo alternative splicing to generate circular RNAs, but their functions remain poorly understood. Here we report that circPRKAA1, a circular RNA (circRNA) derived from the α1 subunit of AMP-activated protein kinase (AMPK), fulfills a fundamental role in maintaining lipid homeostasis. circPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein 1 (mSREBP-1) to enhance the stability of mSREBP-1. Second, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1, and FASN genes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. circPRKAA1 biogenesis is negatively regulated by AMPK activity, with lower AMPK activation in hepatocellular carcinoma tissue frequently associated with elevated circPRKAA1 expression. This work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.

KCTD9 inhibits the Wnt/ß-catenin pathway by decreasing the level of ß-catenin in colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of ß-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of ß-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of ß-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between ß-catenin and ZNT9, thereby leading to decreased ß-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/ß-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.

miRNA-708 functions as a tumor suppressor in colorectal cancer by targeting ZEB1 through Akt/mTOR signaling pathway.

BACKGROUND: Colon cancer, or colorectal cancer (CRC), is a type of cancer that develops from large bowel. Previous data has demonstrated that microRNAs (miRNAs) may be involved in the formation and progression of CRC. The deregulation of miR-708 has been identified in multiple types of cancer. However, to the best of our knowledge, there are no data concerning the expression and role of miR-708 in CRC. METHODS: In this study, RT-PCR and Flow Cytometry were used to examine the expression and role of miR-708 and ZEB1 in proliferation and apoptosis. Transwell was used to examine the role of miR-708 and ZEB1 in invasion and migration. Western blot and qRT-PCR were conducted to determine the alteration of protein and miR-708 levels, respectively. RESULTS: MiR-708 was significantly downregulated in CRC tissues and cell lines. The restoration of the expression of miR-708 suppressed cell proliferation, induced apoptosis, and reduced metastasis in CRC in vitro. Additionally, bioinformatics analysis predicted ZEB1 as a novel target gene of miR-708. Furthermore, ZEB1 was upregulated in CRC, which was negatively correlated with miR-708 expression. Further studies showed that the overexpression of miR-708 and silence of ZEB1 inhibited stage of CRC via inhibiting AKT/mTOR signaling pathway in CRC cells. CONCLUSION: Taken together, these results indicate that miR-708 plays an important role in suppressing the development of CRC by directly targeting ZEB1 through AKT/mTOR signaling pathway, suggesting that miR-708 is a novel, effective therapeutic target for treating patients with CRC.

Knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

BACKGROUND: Angiogenic factor with G-patch and FHA domain 1 (AGGF1), as a newly identified human angiogenic factor, is overexpressed in some types of malignant tumors and closely associated with patient's prognosis. However, the mechanisms involved in the regulation of AGGF1 in gastric cancer (GC) still remain unclear. METHODS: In this study, AGGF1 level in GC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). After knockdown of AGGF expression by RNA interference in GC cell lines MKN-45 and MGC-803, wound healing and transwell assays were conducted to examine the effects of AGGF1 on migration and invasion. Tumor growth was assessed in a mouse xenograft model in vivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Wnt/ß-catenin pathway were detected by western blot and qRT-PCR. RESULTS: Compared to those in normal groups, the protein and mRNA of AGGF1 expression levels were significantly higher both in GC tissues and cell lines (all P < 0.05). Knockdown of AGGF1 dramatically inhibited the invasion and migration of MKN-45 and MGC-803 cells (all P < 0.01) in vitro, and suppressed the tumor growth of nude mice xenograft model in vivo. Western blot revealed alterations in EMT biomarkers, suggesting the role of AGGF1 in EMT. Moreover, we found that downregulated expression of AGGF1 attenuated Wnt/ß-catenin related protein expression. CONCLUSIONS: Collectively, knockdown of AGGF1 inhibits the invasion and migration of gastric cancer via epithelial-mesenchymal transition through Wnt/ß-catenin pathway.

MicroRNA-585 suppresses tumor proliferation and migration in gastric cancer by directly targeting MAPK1.

Increasing evidence reveals that microRNA contributes to the development and progression of gastric cancer (GC), but the roles of miR-585 in GC remain unclear. In this study, we confirmed that miR-585 was down-regulated in GC tissues and cell lines and that miR-585 expression was related to extent of invasion, TNM stage, lymph node invasion and poor prognosis. Our results showed that miR-585 inhibits the proliferation and migration of GC, and MAPK1 is a direct and functional target of miR-585. Our study sheds light on the role of miR-585 as a suppressor for tumor growth and metastasis and raises the intriguing possibility that miR-585 may serve as a new potential marker for monitoring and treating GC.

Martrilin-3 (MATN3) Overexpression in Gastric Adenocarcinoma and its Prognostic Significance.

BACKGROUND The aim of this study was to investigate the expression level of martrilin-3 (MATN3) in patients with gastric adenocarcinoma (GAC) and to investigate the prognostic significance of MATN3. MATERIAL AND METHODS Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were used to predict the expression and prognostic value of MATN3 mRNA in GAC patients. Seventy-six GAC patients had GAC tissue samples and paired adjacent normal tissue samples collected retrospectively to examine the MATN3 protein expression level by immunohistochemical staining. Furthermore, Kaplan-Meier univariate and Cox multivariate analyses were used to verify the correlation between MATN3 expression and clinicopathological parameters of GAC patients and the prognostic significance of MATN3. RESULTS The GEO and TCGA data predicted that MATN3 mRNA levels were significantly higher in GAC tissue compared to normal tissue (all p<0.05). Further survival analyses showed that GAC patients with high mRNA expression of MATN3 had significantly lower disease-free survival (DFS) and overall survival (OS) time than those with low mRNA expression of MATN3 (all p<0.05). Subsequent immunohistochemical staining results confirmed that the MATN3 protein levels in GAC tissues were highly expressed (p=0.000) compared to normal tissues. In addition, GAC patients with high protein expression of MATN3 had remarkably decreased OS compared to patients with low protein expression of MATN3 (p=0.000). Univariate and multivariate survival analyses revealed that MATN3 high expression could be used as an independent predictor of poor prognosis in GAC patients (all p=0.000). CONCLUSIONS This study confirmed that MATN3 protein was highly expressed in GAC patients, and MATN3 overexpression could be used as an independent predictor of poor prognosis in GAC patients.

High Expression of Angiogenic Factor with G-Patch and FHA Domain1 (AGGF1) Predicts Poor Prognosis in Gastric Cancer.

BACKGROUND Angiogenic factor with G-patch and FHA domain1 (AGGF1 or VG5Q) is a newly identified human angiogenic factor. The aim of this study was to explore AGGF1 expression level in gastric cancer and detect its correlation with the prognosis. MATERIAL AND METHODS Immunohistochemistry was performed to detect AGGF1 level in gastric cancer and its adjacent noncancerous samples of 198 cases, and the relationships among the expression levels of AGGF1, vascular endothelial growth factor (VEGF), and prognosis were analyzed. RESULTS Expression of AGGF1 in gastric cancer samples was significantly higher than that in adjacent noncancerous samples (P<0.001). The overall survival rate (OS) of patients with high AGGF1 expression was significantly lower than that of patients with low AGGF1 expression (P=0.000). The Cox model analysis demonstrated that expression of AGGF1 was an independent biomarker for prediction of patients' survival in gastric cancer. CONCLUSIONS High expression of AGGF1 predicts poor prognosis in gastric cancer patients. AGGF1 can be used as an independent factor to predict postoperative survival of patients with gastric cancer.

Laparoscopy-assisted D2 radical distal gastrectomy for gastric cancer (Billroth II anastomosis).

Laparoscopic radical gastrectomy has been increasingly applied in China. However, how to reduce surgery-related trauma, shorten operative time and achieve the long-term prognosis equal to the conventional open surgery is still hot research topics. Along with the change in learning curve and the optimization of endoscopic techniques, laparoscopic lymph node dissection can achieve or even exceed the extent that can be achieved in open surgery. Therefore, it has gradually replaced the conventional digestive tract reconstruction using an auxiliary incision. By completing the laparoscopic digestive tract reconstruction with EndoGIA, we describe the laparoscopy-assisted D2 radical distal gastrectomy for gastric cancer (Billroth II anastomosis).