Loss of Claudin-1 incurred by DNMT aberration promotes pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most malignant and deadly tumors of digestive system with complex etiology and pathogenesis. Dysregulations of oncogenes and tumor suppressors due to epigenetic modifications causally affect tumorogenesis; however the key tumor suppressors and their regulations in PC are only partially defined. In this study, we found that Claudin-1 (encoded by CLDN1 gene) was significantly suppressed in PC that correlated with a poor clinical prognosis. Claudin-1 knockdown enhanced PC cell proliferation, migration, and stemness. Pancreatic specific Cldn1 knockout in KPC (LSLKrasG12D/Pdx1-Cre/Trp53R172H+) and KC (LSLKrasG12D/Pdx1-Cre) mice reduced mouse survival, promoted acinar-to-ductal metaplasia (ADM) process, and accelerated the development of pancreatic intraepithelial neoplasia (PanIN) and PC. Further investigation revealed that Claudin-1 suppression was mainly caused by aberrant DNA methylatransferase 1 (DNMT1) and DNMT3A elevations and the resultant CLDN1 promoter hypermethylation, as a DNMT specific inhibitor SGI-1027 effectively reversed the Claudin-1 suppression and inhibited PC progression both in vitro and in vivo in a Claudin-1 preservation-dependent manner. Together, our data suggest that Claudin-1 functions as a tumor suppressor in PC and its epigenetic suppression due to DNMT aberrations is a crucial event that promotes PC development and progression.

Age-stratified risk factors of re-intervention for uterine fibroids treated with high-intensity focused ultrasound.

OBJECTIVE: To estimate the rate and risk factors of re-intervention for patients with uterine fibroids (UFs) undergoing high-intensity focused ultrasound (HIFU) at different age distributions. METHOD: A retrospective cohort study was conducted in Nanchong Central Hospital, recruiting a total of 672 patients with UFs undergoing HIFU from June 2017 to December 2019. Using univariate and multivariate logistic regression, risk factors for re-intervention were assessed. RESULTS: Among 401 patients with UFs who completed the follow-up visits (median 47 months, range 34-61), 50 (12.46%) patients underwent re-intervention (such as high-intensity focused ultrasound, uterine artery embolization, myomectomy and hysterectomy). In the different age distributions, the re-intervention rate was 17.5% (34/194) in patients aged <45 years and 7.7% (16/207) in those aged ≥45 years. Regarding the younger patient group (aged <45 years), hypo- or iso-intensive fibroids in T2-weighted magnetic resonance imaging (T2WI) intensity may elevate the risk of re-intervention for UFs (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.37-6.62; P = 0.007). Among the older patient group (aged ≥45 years), preoperative anemic patients had an increased risk of re-intervention compared with those without anemia (OR 3.30, 95% CI 1.01-10.37; P = 0.041). CONCLUSION: The re-intervention rate of HIFU decreased with increasing age. Among those aged <45 years, T2WI intensity was the independent risk factor for re-intervention, and among those aged ≥45 years, preoperative anemic status may be related to re-intervention outcome.

Nanoclay Drug-Delivery System Loading Potassium Iodide Promotes Endocytosis and Targeted Therapy in Anaplastic Thyroid Cancer.

The rapid proliferative biological behavior of primary foci of anaplastic thyroid cancer (ATC) makes it a lethal tumor. According to the specific iodine uptake capacity of thyroid cells and enhanced endocytosis of ATC cells, we designed a kind of nanoclay drug-loading system and showed a promising treatment strategy for ATC. Introducing potassium iodide (KI) improves the homoaggregation of clay nanoparticles and then affects the distribution of nanoparticles in vivo, which makes KI@DOX-KaolinMeOH enriched almost exclusively in thyroid tissue. Simultaneously, the improvement of dispersibility of KI@DOX-KaolinMeOH changes the target uptake of ATC cells by improving the endocytosis and nanoparticle-induced autophagy, which regulate the production of autolysosomes and autophagy-enhanced chemotherapy, eventually contributing to a tumor inhibition rate of more than 90% in the primary foci of ATC. Therefore, this facile strategy to improve the homoaggregation of nanoclay by introducing KI has the potential to become an advanced drug delivery vehicle in ATC treatment.

A Retrospective Study on the Three-Port Technique of Laparoscopic Common Bile Duct Exploration for the Management of Cholelithiasis and Choledocholithiasis.

Background: Laparoscopic cholecystectomy (LC) with laparoscopic common bile duct exploration (LCBDE) is convenient in treating cholelithiasis and choledocholithiasis due to its advantage of accelerated recovery. This retrospective study aimed to summarize the experience of cholelithiasis and choledocholithiasis treatment via three-port approach of LCBDE in Eastern China. Methods: Patients diagnosed with cholelithiasis and choledocholithiasis between July 2019 and October 2021 were included. Patients who received LC+LCBDE+primary suturing of the common bile duct (CBD) via a three-port approach were assigned to the LCBDE-P group, and those who received LC+LCBDE+T-tube drainage of CBD comprised the LCBDE-T group. The measurement data were compared between the two groups. P-values <0.05 indicated statistical significance. Results: A total of 88 patients were divided into two groups: LCBDE-P (n=50) and LCBDE-T (n=38). Multiple logistic regression analysis showed that LCBDE-P is associated with a shorter length of stay (OR=0.115, 95% CI: 0.040-0.329, P<0.001) and lower hospitalization costs (OR=0.120, 95% CI: 0.041-0.357, P<0.001). No significant differences between the two groups were detected in the operation time, intraoperative hemorrhage, clearance rate of CBD stones, postoperative liver function, and postoperative complications (P>0.05). Conclusion: The three-port approach of LCBDE is a safe and feasible strategy for managing cholelithiasis and choledocholithiasis. Compared to LCBDE-T, LCBDE-P reduces the length of hospital stay and medical costs during hospitalization.

Age-based factors modulating the required thyroxine dose to achieve thyrotropin suppression in intermediate-and high-risk papillary thyroid cancer.

Background: Guidelines widely recommend thyrotropin suppression to reduce the risk of recurrence in intermediate- and high-risk papillary thyroid cancer (PTC) after total thyroidectomy. However, an insufficient or excessive dosage may result in a number of symptoms/complications especially in older patients. Patients and methods: We constructed a retrospective cohort including 551 PTC patient encounters. Using propensity score matching and logistic regression models, we determined the independent risk factors affecting levothyroxine therapy at different ages. Our outcomes included: expected TSH level and an unexpected TSH level, which was based on the initial thyroid-stimulating hormone (TSH) goal< 0.1 mIU/L with usual dosage of L-T4 (1.6 µg/kg/day). Results: From our analysis, more than 70% of patients undergoing total thyroidectomy did not achieve the expected TSH level using an empirical medication regimen, and the effect of the drug was affected by age (odds ratio [OR], 1.063; 95% CI, 1.032-1.094), preoperative TSH level (OR, 0.554; 95% CI, 0.436-0.704) and preoperative fT3 level (OR, 0.820; 95% CI, 0.727-0.925). In patients with age < 55 years old, preoperative TSH level (OR, 0.588; 95% CI, 0.459-0.753), and preoperative fT3 level (OR, 0.859; 95% CI, 0.746-0.990) were two independent protective factors, while, in patients with age ≥ 55 years old, only preoperative TSH level (OR, 0.490; 95% CI, 0.278-0.861) was the independent protective factors to achieve expected TSH level. Conclusion: Our retrospective analysis suggested the following significant risk factors of getting TSH suppression in PTC patients: age (≥55 years), lower preoperative TSH and fT3 levels.

The role of preoperative biliary drainage on postoperative outcome after pancreaticoduodenectomy in patients with obstructive jaundice.

Background: The role of preoperative biliary drainage (PBD) on obstructive jaundice patients is still controversial. The aim of this retrospective study is to clarify the effect of PBD on postoperative outcomes of pancreaticoduodenectomy (PD) and explore a reasonable PBD strategy for periampullary carcinomas (PAC) patients with obstructive jaundice before surgery. Methods: A total of 148 patients with obstructive jaundice who underwent PD were enrolled in this research and divided into drainage group and no-drainage group according to whether they received PBD. Patients who received PBD were classified into long-term group (>2 weeks) and short-term group (≤2 weeks) according to PBD duration. The clinical data of patients were statistically compared between groups to explore the influence of PBD and its duration. Analysis of pathogens in bile and peritoneal fluid was performed to probe the role of bile pathogens in opportunistic pathogenic bacterial infection after PD. Results: Of all, 98 patients underwent PBD. The mean duration between drainage and surgery was 13 days. Regarding postoperative outcomes, the incidence of postoperative intra-abdominal infection was significantly higher in the drainage group than the no-drainage group (P=0.026). In patients with total bilirubin (TB) less than 250 µmol/L, postoperative intra-abdominal infection was more frequently observed in the drainage group compared to the no-drainage group (P=0.022). Compared to the short-term drainage group, the proportion of positive ascites culture was significantly higher in the long-term drainage group (P=0.022). There were no statistically significant differences in postoperative complications between short-term group and no-drainage group. The most frequent pathogens detected in bile were Klebsiella pneumoniae, hemolytic Streptococcus and Enterococcus faecalis. The most commonly detected pathogens in peritoneal fluid were Klebsiella pneumoniae, Enterococcus faecalis and Staphylococcus epidermidis which appeared to have a high agreement with pathogens in preoperative bile cultures. Conclusions: Routine PBD should not be performed in obstructive jaundice PAC patients with TB less than 250 µmol/L. For patients with indications for PBD, the drainage duration should be controlled within 2 weeks. Bile bacteria may represent a major source of opportunistic pathogenic bacteria infection after PD.

The impact of laparoscopic versus open inguinal hernia repair for inguinal hernia treatment: A retrospective cohort study.

Objectives: Although laparoscopic inguinal hernia repair (LIHR) has been widely accepted for treating inguinal hernia, the procedure remains very technical and challenging. The present study aimed to assess the effect of LIHR in relation to operation time, intraoperative hemorrhage and postoperative hospitalization. Methods: A total of 503 patients with inguinal hernia admitted at the Wuxi Rehabilitation Hospital between June 2019 and July 2021 were included in this retrospective cohort study. Binary logistic and linear regressions were used for categorical and continuous outcomes, respectively. The learning curve was drawn by cumulative sum analysis. Results: Multivariate logistic regression analysis identified LIHR as an independent factor associated with prolonging operation time (odd ratio [OR] = 1.750, 95% confidence interval [CI]: 1.215-2.520, p = 0.003) and decreasing intraoperative hemorrhage levels (OR = 0.079, 95 CI: 0.044-0.142, p < 0.001). Multivariate linear regression identified LIHR (Coefficient = -0.702, 95% CI: [-1.050] to [-0.354], p < 0.001) as an independent factor for shortening postoperative hospitalization time. After learning curve, LIHR (OR = 1.409, 95% CI: 0.948 to 2.094, p = 0.090) no longer resulted as a risk factor prolonging operation time. Conclusions: LIHR is an important independent predictive factor for decreasing intraoperative hemorrhage levels and shortening postoperative hospitalization time. Additionally, LIHR does not prolong operation time after the learning curve.

Postoperative complications and short-term prognosis of laparoscopic pancreaticoduodenectomy vs. open pancreaticoduodenectomy for treating pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Although laparoscopic pancreaticoduodenectomy (LPD) has been accepted worldwide for treating pancreatic ductal adenocarcinoma (PDA), it is a very technical and challenging procedure. Also, it is unclear whether LPD is superior to open pancreaticoduodenectomy (OPD). This study summarized the experience and efficacy of LPD for treating PDA in our medical center. METHODS: This retrospective cohort study included patients with PDA admitted at the Affiliated Hospital of Jiangnan University from October 2019 and January 2021. Patients received either LPD or OPD. Clinical outcomes (operation time, duration of anesthesia, intraoperative hemorrhage), postoperative complications, and short-term outcomes were compared. Cox proportional hazard model and Kaplan-Meier method were used to analyze overall survival (OS) and progression-free survival (PFS). RESULTS: Among the PDA patients, 101 patients underwent surgical treatment, 4 patients converted from LPD to OPD, and 7 of them received conservative treatment. Forty-six patients were cured of LPD, and 1 of them died shortly after the operation. Moreover, 44 patients received OPD, and there were 2 postoperative deaths. There were significant differences in the location of the operation time, duration of anesthesia, postoperative hemorrhage, abdominal infections, and postoperative pneumonia between the two groups (all p < 0.05). Multivariate analysis showed that LPD was an independent factor negatively correlated with the incidence of pneumonia (relative risk (RR) = 0.072, 95%CI: 0.016-0.326, p = 0.001) and abdominal infection (RR = 0.182, 95%CI: 0.047-0.709, p = 0.014). Also, there were no differences in OS (hazard ratio (HR) = 1.46, 95%CI: 0.60-3.53, p = 0.40) and PFS (HR = 1.46, 95%CI: 0.64-3.32, p = 0.37) at 12 months between the two groups. CONCLUSIONS: LPD could be efficacy and feasible for managing selected PDA patients. Also, LPD has a better effect in reducing postoperative pneumonia and abdominal infection compared to OPD.

Association of Ozone Exposures with the risk of thyroid nodules in Hunan Province: a population-based cohort study.

BACKGROUND: Increasing evidence associates air pollution with thyroid dysfunction, whereas the potential relationship between exposure to ozone (O3) and Thyroid Nodules (TNs) is unclear. METHODS: This retrospective cohort study investigated the association between O3 exposure and TNs in Hunan province, enrolling 191,357 Chinese adults who lived in Hunan province from January 2009 to December 2019 and received voluntary medical examinations. Individual exposure levels to O3 from 2010 to 2019 were measured on account of participants' residential addresses at the district level. Associations of O3 exposure with the risk of incidental TNs were assessed by restricted cubic splines and surveyed as odds ratios after adjusting for demographic factors. RESULTS: In total, 81,900 adults were newly diagnosed with TNs during the study period. Age-standardized TNs detection rate in Hunan province increased from 25.9 to 46.3% between 2010 and 2019, with the greatest annual percent change being 8.1 [95% CI, 7.3-8.8]. A similar trend has been found in all tumor sizes, ages, and both sexes. O3 exposure presented a statistically significant dose-dependent positive correlation (greater than 0.036 ppm) with TNs. Similarly, long-term exposure to high levels of O3 (1-year average O3 concentrations exceeding 0.0417 ppm) was found positively associated with increased TSH levels. CONCLUSIONS: High-level O3 exposure in the long term was associated with an increase in TSH. Consequently, increased TSH was related to the increased risk of TNs. Being exposed to high-level O3 in the long term was related to the increased detection rates of TNs in Hunan province, which could be mediated by TSH.

Development and validation of a nomogram for predicting post-operative abdominal infection in patients undergoing pancreaticoduodenectomy.

AIM: The aim of this retrospective study is to develop and validate a predictive nomogram for predicting the risk of post-operative abdominal infection (PAI) in patients undergoing pancreaticoduodenectomy (PD). METHODS: A total of 360 patients who underwent PD were enrolled into this research and randomly divided into the development and validation group. The clinical data of patients were statistically compared and the nomogram was constructed based on the results of multivariate logistic regression analysis and stepwise (stepAIC) selection. The nomogram was internally and crossly validated by the development and validation cohort. The discriminatory ability of the nomogram was estimated by AUC (Area Under the receiver operating characteristic Curve), calibration curve and decision curve analysis. RESULTS: After PD, post-operative abdominal infection occurred in 33.89% (n = 122) of patients. The nomogram showed that preoperative biliary drainage and C-reactive protein (CRP), direct bilirubin (DB), alkaline phosphatase (AKP) levels on the 3rd postoperative day (POD3) were independent prognostic factors for abdominal infection after PD. The internal and cross validation of Receiver Operating Characteristic (ROC) curve was statistically significant (AUC = 0.723 and 0.786, respectively). The calibration curves showed good agreement between nomogram predictions and actual observations. The decision curves showed that the nomogram was of great clinical value. CONCLUSION: A nomogram based on perioperative risk factors such as preoperative biliary drainage, CRP, DB and AKP could simply and accurately predict the risk degree of PAI in patients undergoing PD.

Pressure increases PD-L1 expression in A549 lung adenocarcinoma cells and causes resistance to anti-ROR1 CAR T cell-mediated cytotoxicity.

Due to the abnormal vasculation and proliferation, the tumor microenvironment is hypoxic, lacking nutrients, and under high interstitial pressure. Compared to oxygen and nutrients, the effect of pressure on cancer biology remains poorly studied. Here we constructed αROR1-CAR T cells and co-cultured with A549 cells with and without elevated pressure. We then measured apoptosis and cell death by flow cytometry and luciferase activity. We also measured cytokine (IL-2, IFN-γ, and TNF-α) release by ELISA. The results show that pressure-preconditioned A549 cells are much resistant to αROR1-CAR T cell-mediated cytotoxicity. Pressure preconditioning does not appear to affect the expression of αROR1-CAR or cytokine production. However, pressure preconditioning upregulates PD-L1 expression in A549 cells and decreases cytokine release from αROR1-CAR T cells. In addition, Pembrolizumab and Cemiplimab that block PD-1::PD-L1 interaction increase the cytokine production in αROR1-CAR T cells, increase the apoptotic cell death in A549 cells, and improve the αROR1-CAR T-mediated cytotoxicity. In xenograft mice, pressure preconditioning increases tumorigenesis of A549 cells, which can be blocked by a combined therapy using Pembrolizumab and αROR1-CAR T cells. Together, our studies suggest that elevated pressure in the tumor microenvironment could blunt the T cell therapy by upregulating PD-L1 expression, which could be overcome by combining CAR T therapy with immune checkpoint inhibitors.

Comparisons of Outcomes Between Adolescent and Young Adult with Older Patients After Radical Resection of Pancreatic Ductal Adenocarcinoma by Propensity Score Matching: A Single-Center Study.

PURPOSE: Adolescent and young adult (AYA) pancreatic ductal adenocarcinoma (PDAC) occurs in patients below 40 years old. Whether AYA patients have worse outcomes compared with older patients is still controversial. The purpose of this study is to compare the outcomes of AYA patients and older patients after radical surgery for PDAC. METHODS: A single-center, retrospective, cohort study was conducted in patients who underwent radical surgery for PDAC in Xiangya Hospital Central South University from January 2007 to December 2019. The clinicopathological data and results of patients with PDAC were collected and analyzed retrospectively. They were divided into AYA group and older group based on age (<40, AYA group; ≥40, older group). Based on all the considered covariates except age, we estimated 1:2 case propensity score matching (PSM). RESULTS: A total of 1033 cases were enrolled, 46 cases (4.45%) in the AYA group. Both before and after PSM, the AYA patients have a higher preoperative CA19-9 than the older patients (P < 0.001) and (P < 0.001). Pathological results showed that AYA group had a higher microvascular invasion rate (P < 0.001 and P = 0.045) than older group. The median time of overall survival (OS) in AYA group and older group were 13 months (95% CI = 11.50-14.50) and 14 months (95% CI = 13.50-14.50), respectively. Additionally, AYA group have a worse 2-year OS rate than older group (8.70% vs 25.23%, P = 0.011 and 8.70% vs 25.00%, P = 0.023). According to the Log rank test, AYA group have a worse cumulative OS rate than older group (P = 0.002) and (P = 0.030), respectively. CONCLUSION: PDAC might be more aggressive in AYA, and the cumulative OS after radical PDAC surgery in AYA patients is worse than that in older patients.

Comprehensive Analysis of Prognostic Alternative Splicing Signature Reveals Recurrence Predictor for Papillary Thyroid Cancer.

BACKGROUND: Alternative splicing (AS) plays a key role in the diversity of proteins and is closely associated with tumorigenicity. The aim of this study was to systemically analyze RNA alternative splicing (AS) and identify its prognostic value for papillary thyroid cancer (PTC). METHODS: AS percent-splice-in (PSI) data of 430 patients with PTC were downloaded from the TCGA SpliceSeq database. We successfully identified recurrence-free survival (RFS)-associated AS events through univariate Cox regression, LASSO regression and multivariate regression and then constructed different types of prognostic prediction models. Gene function enrichment analysis revealed the relevant signaling pathways involved in RFS-related AS events. Simultaneously, a regulatory network diagram of AS and splicing factors (SFs) was established. RESULTS: We identified 1397 RFS-related AS events which could be used as the potential prognostic biomarkers for PTC. Based on these RFS-related AS events, we constructed a ten-AS event prognostic prediction signature that could distinguish high-and low-risk patients and was highly capable of predicting PTC patient prognosis. ROC curve analysis revealed the excellent predictive ability of the ten-AS events model, with an area under the curve (AUC) value of 0.889; the highest prediction intensity for one-year RFS was 0.923, indicating that the model could be used as a prognostic biomarker for PTC. In addition, the nomogram constructed by the risk score of the ten-AS model also showed high predictive efficiency for the prognosis of PTC patients. Finally, the constructed SF-AS network diagram revealed the regulatory role of SFs in PTC. CONCLUSION: Through the limited analysis, AS events could be regarded as reliable prognostic biomarkers for PTC. The splicing correlation network also provided new insight into the potential molecular mechanisms of PTC.

Androgen Receptors Act as a Tumor Suppressor Gene to Suppress Hepatocellular Carcinoma Cells Progression via miR-122-5p/RABL6 Signaling.

Hepatocellular carcinoma (HCC) is a malignant tumor with a high degree of malignancy and a poor prognosis. Androgen receptor (AR) has been reported to play important roles in the regulation of the progression of HCC, but the underlying mechanisms of how AR regulates HCC initiation, progression, metastasis, and chemotherapy resistance still need further study. Our study found that AR could act as a tumor suppression gene to suppress HCC cells invasion and migration capacities via miR-122-5p/RABL6 signaling, and the mechanism study further confirmed that miR-122-5p could suppress the expression of RABL6 to influence HCC cells progression by directly targeting the 3'UTR of the mRNA of RABL6. The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the clinical data gotten from online databases based on TCGA samples also confirmed the linkage of AR/miR-122-5p/RABL6 signaling to the HCC progression. Together, these findings suggest that AR could suppress HCC invasion and migration capacities via miR-122-5p/RABL6 signaling, and targeting this newly explored signaling may help us find new therapeutic targets for better treatment of HCC.

Pan-cancer analysis of the oncogenic role of discs large homolog associated protein 5 (DLGAP5) in human tumors.

BACKGROUND: In recent years, there have been many studies on the relationship between DLGAP5 and different types of cancers, yet there is no pan-cancer analysis of DLGAP5. Therefore, this study aims to analyze the roles of DLGAP5 in human tumors. METHODS: Firstly, we evaluated the expression level of DLGAP5 in 33 types of tumors throughout the datasets of TCGA (Cancer Genome Atlas) and GEO (Gene Expression Synthesis). Secondly, we used the GEPIA2 and Kaplan-Meier plotter to conduct Survival prognosis analysis. Additionally, cBioPortal web was utilized to analyze the genetic alteration of DLGAP5, after which we selected hepatocellular carcinoma (HCC) cell lines to define the function of DLGAP5. Last but not least, we performed immune infiltration analysis and DLGAP5-related gene enrichment analysis. RESULTS: DLGAP5 is highly expressed in most type of cancers, and there is a significant correlation between the expression of DLGAP5 and the prognosis of cancer patients. We have observed that DLGAP5 promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cell lines. We also found that DLGAP5 expression was related with the CD8+ T-cell infiltration status in kidney renal clear cell carcinoma, uveal melanoma, and thymoma, and cancer-associated fibroblast infiltration was observed in breast invasive carcinoma, kidney renal papillary cell carcinoma and testicular germ cell tumors. In addition, enrichment analysis revealed that cell cycle- and oocyte meiosis-associated functions were involved in the functional mechanism of DLGAP5. CONCLUSIONS: Taken together, our unpresented pan-cancer analysis of DLGAP5 provides a relatively integrative understanding of the oncogenic role of DLGAP5 in various tumors. DLGAP5 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of DLGAP5 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

Zinc finger protein 91 accelerates tumour progression by activating ß-catenin signalling in pancreatic cancer.

OBJECTIVES: ZFP91, an E3 ligase, has been reported to possess cancer-promoting functions. This study aimed to elucidate the exact role of ZFP91 in tumour progression of pancreatic cancer and underlying mechanisms. MATERIALS AND METHODS: We analysed the correlation between ZFP91 expression and pancreatic cancer through TCGA and GEO data sets. Growth curve, colony formation, wound healing and transwell invasion assays were conducted to evaluate proliferation, migration and invasion of lentivirus transfected pancreatic cancer cells. GSEA and Western blot analysis were performed to validate the regulatory effect of ZFP91 on ß-catenin. Drug response curve and orthotopic implantation model reflected the sensitivity of chemotherapies. RESULTS: ZFP91 overexpression is prevalent in pancreatic cancer and negatively correlated with overall survival. ZFP91 knock-down attenuated proliferation, migration and invasion of pancreatic cancer cells. ß-catenin was a downstream gene of ZFP91, and its agonist could reverse the phenotype. ZFP91 promoted EMT and chemoresistance in pancreatic cancer. CONCLUSIONS: We demonstrated that ZFP91 promoted pancreatic cancer proliferation, migration and invasion through activating ß-catenin signalling. EMT and chemoresistance were also regulated by ZFP91. ZFP91 might be a potential therapeutic target for pancreatic cancer.

Mind Bomb 1 Promotes Pancreatic Cancer Proliferation by Activating ß-Catenin Signaling.

Mind bomb 1 (MIB1), an E3 ligase, plays a vital role in chemo-resistance and cancer metastasis. According to The Cancer Genome Atlas (TCGA), MIB1 gene is preferentially amplified in pancreatic cancer. Copy number alterations in MIB1 gene are associated with worse survival. Gene Expression Omnibus (GEO) also showed that pancreatic cancer with high mRNA level of MIB1 tend to be more resistant to gemcitabine and higher mRNA levels of MIB1 are found in pancreatic tumors compared with adjacent normal tissues. MIB1 knockdown (KD) in Panc-1 and HPAF2 cell lines significantly inhibit proliferation and colony formation of pancreatic cancer. The gene set enrichment analysis (GSEA) has also showed that ß-catenin is the downstream of MIB1. Western blot analysis showed that total and active ß-catenin levels are decreased in MIB1 KD cells. ß-catenin inhibitor also inhibits proliferation of Panc-1 and HPAF2 cells. We in this study implanted HPAF2 scramble and MIB1 KD cells orthotopically in athymic nude mice. Gemcitabine was used to treat the mice. Results revealed that after MIB1 KD HPAF2 cells were more sensitive to gemcitabine. In conclusion, we demonstrated that MIB1 promotes pancreatic cancer proliferation through activating ß-catenin signaling. MIB1 may thus be a therapeutic target in pancreatic cancer therapy.

MUC1 promotes glycolysis through inhibiting BRCA1 expression in pancreatic cancer.

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.