Mass spectrum analysis of membrane proteins reveals that CASK, CD36 and EPB42 are differentially expressed in pancreatic adenocarcinoma.

Pancreatic cancer is one of the most life-threatening malignancies worldwide. Despite advances in checkpoint immunotherapy for patients with cancer, the current immunotherapies have demonstrated limited benefits for the treatment of pancreatic cancer. Apart from the intricate microenvironments that restrict T-cell function, membrane proteins other than programmed death-ligand 1 may also facilitate immune escape of tumor cells. The present study investigated the membrane proteins of seven paired pancreatic adenocarcinoma (PAAD) and adjacent normal tissues with mass spectrometry, and identified 10 up-and eight downregulated membrane proteins in PAAD. Together with the online database analysis, the results showed that the CASK protein was upregulated in PAAD samples and cell lines, and predicts poor outcomes in patients with PAAD. Furthermore, the results exhibited downregulated CD36 and EPB42 in PAAD samples and cell lines, and higher levels of CD36. EPB42 was shown to predict improved survival outcomes in patients with PAAD. Overall, the results of the present study revealed PAAD-specific membrane proteins as potential diagnostic markers and drug-targets for the immunotherapy of pancreatic cancer.

Exosomal piRNA profiling revealed unique circulating piRNA signatures of cholangiocarcinoma and gallbladder carcinoma.

Cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC) are biliary tract cancers with poor five-year survival and high recurrence rates. Both CCA and GBC patients suffer from lack of circulating diagnostic biomarkers at the early stage. Extracellular vesicles, especially exosomes, have been emerged as promising diagnostic sources for cancers due to easy and quick accessibility. Hence, identification of exosomal biomarkers provides a novel strategy for CCA and GBC diagnosis. Here, five CCA patients and four GBC patients were enrolled for exosomal small RNA sequencing. Our data showed that exosomal piwi-interacting RNA (piRNA) populations were altered in the plasma of CCA and GBC patients. In comparison to healthy individuals, 694 and 323 piRNAs were upregulated in CCA and GBC, respectively, while 36 and 191 piRNAs were downregulated. Interestingly, sequencing results predicted that piR-2660989, piR-10506469, piR-20548188, piR-10822895, piR-hsa-23209, and piR-18044111 were upregulated in both CCA and GBC plasma. Importantly, we further included blood samples from 50 health individuals, 40 CCA patients, and 25 GBC patients and found that piR-10506469 were significantly increased in the exosomes of plasma from both CCA and GBC patients. Moreover, we analyzed the expression levels of differentially expressed exosomal piRNAs in the plasma of CCA and GBC patient before and after surgeries and found that piR-10506469 and piR-20548188 were significantly decreased in patients underwent surgeries. Taken together, our data revealed that exosomal piRNAs those are differentially expressed in CCA and GBC plasma may serve as potential biomarkers for the diagnosis of CCA and GBC.

Correction: ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ZNF774 is a potent suppressor of hepatocarcinogenesis through dampening the NOTCH2 signaling.

Discerning oncogenic drivers from passengers remain a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), which is the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. Genome-wide identification of the transcriptional targets of the ZNF774/NuRD complex by ChIP-seq indicated that ZNF774 represses a cohort of genes including NOTCH2 that are critically involved in the growth and mobility of HCC. We demonstrated that the ZNF774/NuRD complex inhibits the proliferation and invasion of HCC cells in vitro and suppresses HCC growth and metastasis in vivo. Importantly, the expression of ZNF774 is significantly downregulated in HCC, and low ZNF774 expression strongly correlated with high NOTCH2 expression, advanced pathological stages, and poor overall survival of the patients. Together, these results uncover a key role for the ZNF774/NuRD-NOTCH2 axis in hepatocarcinogenesis.

Preoperative maximum standardized uptake value and carbohydrate antigen 19-9 were independent predictors of pathological stages and overall survival in Chinese patients with pancreatic duct adenocarcinoma.

BACKGROUND: Purpose of this study was to analyze whether preoperative maximum standardized uptake value (SUVmax) and carbohydrate antigen 19-9 (CA19-9) levels might provide prognostic information in Chinese patients with pancreatic duct adenocarcinoma (PDAC) after pancreaticoduodenectomy (PD). METHODS: Standard PD was performed on 109 patients with PDAC by the same operative team, and all patients received preoperative positron emission tomography/computed tomography examination and blood test. RESULTS: Patients had a mean age of 59 ± 9.35 years. Females accounted for 38.5%. Mean levels of SUVmax, carcino-embryonic antigen (CEA) and CA19-9 were 5.70 ± 2.76, 3.95 ± 4.16ng/mL and 321.62 ± 780.71kU/L. In univariate Logistic regression analysis, preoperative SUVmax, CEA and CA19-9 levels (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly related to AJCC stages. Multivariate Logistic regression analysis showed that preoperative SUVmax and CA19-9 levels (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly associated with AJCC stages. Mean overall survival (OS) was 21 ± 14.50 months. In univariate Cox regression analysis, age, SUVmax, CEA and CA19-9 levels before operation (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly related to OS. Multivariate Cox regression analysis showed that age, SUVmax and CA19-9 levels before operation (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly associated with OS. CONCLUSIONS: This study demonstrated that preoperative SUVmax and CA19-9 levels independently predicted pathological stages and OS of patients with PDAC after PD. These preoperative variables might have significant prognostic implication in patients with PDAC after PD. Patients with abnormal SUVmax and CA19-9 levels should be paid special attention to in operative strategy and perioperative management.

GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway.

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis in vitro and in vivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.

MTA2 promotes HCC progression through repressing FRMD6, a key upstream component of hippo signaling pathway.

Discerning oncogenic drivers from passengers remains a major effort in understanding of the essence of the initiation and development of hepatocellular carcinoma (HCC), the most common primary liver malignancy and the third leading cause of cancer mortality worldwide. Here we report that MTA2, Metastasis Associated 1 Family Member 2, is significantly up-regulated in HCC. We show that high level of MTA2 expression is strongly correlated with advanced pathological stages and poor overall survival of the patients. Genome-wide identification of the transcriptional targets of MTA2 by ChIP-seq indicates that MTA2 represses a cohort of genes including FRMD6 that are critically involved in the growth and mobility of HCC. We demonstrate that the MTA2 promotes the proliferation and metastasis of HCC in vitro and in vivo through suppressing Hippo signaling pathway. Together, these results reveal a key role for the MTA2-FRDM6-Hippo axis in human hepatocarcinogenesis.

Application of 18F-FDG PET/CT combined with carbohydrate antigen 19-9 for differentiating pancreatic carcinoma from chronic mass-forming pancreatitis in Chinese elderly.

OBJECTIVE: The current study was designed to analyze the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) combined with carbohydrate antigen 19-9 (CA19-9) in differentiating pancreatic carcinoma (PC) from chronic mass-forming pancreatitis (CMFP) in Chinese elderly. METHODS: As it is impossible to differentially diagnose PC from CMFP, 60 participants older than 65 years with focal pancreatic lesions were scanned by 18F-FDG PET/CT and their CA19-9 levels were tested. Diagnoses of all participants were confirmed by comprehensive methods including aspiration biopsy, surgical pathology, and clinical follow-up of 12 months. Twenty participants with CMFP were included in CMFP group and 40 participants with PC in PC group. RESULTS: In CMFP and PC groups, 46 participants showed increased 18F-FDG uptake, 43 had elevated CA19-9 levels, and 38 participants had both increased 18F-FDG uptake and elevated CA19-9 levels. Standardized uptake value maximum of PC group (5.98±2.27) was significantly different from CMFP group (2.58±1.81, P<0.05). Sensitivity, specificity, and accuracy of 18F-FDG PET/CT in differentiating PC from CMFP were 95%, 60%, and 83.3%, respectively. CA19-9 levels of PC group (917.44±1,088.24) were significantly different from CMFP group (19.09±19.54, P<0.05). Sensitivity, specificity, and accuracy of CA19-9 levels in differentiating PC from CMFP were 87.5%, 60%, and 78.3%, respectively. Sensitivity, specificity, and accuracy of 18F-FDG PET/CT combined with CA19-9 levels in differentiating PC from CMFP were 90%, 90%, and 90%, respectively. CONCLUSION: 18F-FDG PET/CT had reliable sensitivity, specificity, and accuracy in differentiating PC from CMFP, and CA19-9 levels could be helpful in 18F-FDG PET/CT for differentiating PC from CMFP in Chinese elderly. Moreover, 18F-FDG PET/CT combined with CA19-9 levels was found to be an effective method to differentially diagnose PC from CMFP and has paved the way for the timely and safe treatment of PC and CMFP in Chinese elderly.

[Application of ¹8F-fluorodeoxyglucose positron emission tomography/computed tomography in preoperative assessment of hilar cholangiocarcinoma].

OBJECTIVE: To evaluate the value of positron emission tomography/computed tomography (PET/CT) in the preoperative assessment of hilar cholangiocarcinoma (HC). METHODS: A retrospective analysis was performed for 32 HC patients. There were 14 females and 18 males with a mean age of 56 years old. All cases were confirmed by surgery, pathology or other diagnostic modalities. ¹8F-fluorodeoxyglucose (FDG) PET/CT was performed preoperatively in all patients. The images were interpreted and compared with the operative and pathological outcomes in each case. RESULTS: Among them, according to the Bismuth-Corlette classification, the number of types I, II, IIIa, IIIb and IV patients, were 3, 2, 4, 8 and 15 respectively. Radical tumor resection was performed in 16 patients. Among them, 3, 2, 1, 7 and 3 patient belonged to types I, II, IIIa, IIIb and IV respectively. Seven patients underwent palliative surgery and 9 had only surgical exploration. The detecting accuracy of PET/CT in primary tumors Bismuth-Corlette classification reached 81.25% (26/32). The sensitivity, specificity and accuracy of PET/CT in detecting lymph node metastasis and distant metastasis were 64.7%, 86.7%, 75.0% and 41.7%, 95.0%, 75.0% respectively. The concordance rate of preoperative evaluation of respectability by PET/CT and intraoperative evaluation was 75.0%. No significant difference existed between PET/CT and the surgical and histopathologic findings in the evaluation of curative resectability for HC (χ² = 0.125, P > 0.05). CONCLUSION: ¹8F-FDG PET/CT is of great value in the diagnosis of HC, as well as in detecting lymph node metastasis and distant metastasis. Thus ¹8F-FDG PET/CT is helpful in the preoperative assessment of resectability for HC.

Retroperitoneoscopic pancreatectomy: a new surgical option for pancreatic disease.

OBJECTIVE: The advantage of retroperitoneoscopy in renal and adrenal gland surgery has been widely acknowledged. Retroperitoneoscopy may also be a useful approach to the pancreas, a retroperitoneal organ. This study aims to evaluate the feasibility of retroperitoneoscopic pancreatectomy performed in an animal model and a small patient cohort. METHODS: This study was divided into two stages. Initially, retroperitoneoscopic distal pancreatectomy was performed in 6-month-old Yorkshire breed piglets (n = 5; mean weight, 50 ± 5 kg). Subsequently, seven patients with suspected diagnosis of distal pancreatic lesions were selected between February 2010 and April 2011 to undergo retroperitoneoscopy. Approval was obtained from both the Animal Ethics Committee and the Institutional Review Board. RESULTS: In the animal models, retroperitoneoscopic procedures were accomplished smoothly with short operative time, insignificant blood loss, and only minor complications. In clinical practice, patients with histologically confirmed pancreatic diseases underwent enucleation (n = 2) or distal pancreatectomy with splenic preservation (n = 2). Operative times ranged from 30 to 100 min with controllable blood loss of 10-100 ml. One case of intraoperative retroperitoneal perforation and two cases of pancreatic fistula occurred. All four patients were discharged within 7 days postoperatively. The other three patients with nonpancreatic diseases underwent retroperitoneoscopic resection with excellent clinical outcome. CONCLUSIONS: The results of this preliminary study demonstrate that retroperitoneoscopic pancreatectomy, a novel surgical approach, was feasible and effective in selected patients. The advantages of this approach include acceptable operating time, insignificant blood loss, simple manipulations, minor complications, and excellent postoperative recovery time. Additionally, this study suggests that retroperitoneoscopy could also be feasible for treatment of retroperitoneal nonpancreatic diseases.