Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis; nearly 80% patients have regional or distant metastasis when diagnosed. Tumor microenvironment (TME) alteration and epithelial-to-mesenchymal transition (EMT) have been reported to play a key role in cancer metastasis. However, the correlation between TME and EMT was poorly studied in PDAC. This study aims to explore the correlation between EMT markers and TME alteration, mainly including macrophage polarization and PD-L1 expression change, in primary and metastatic PDAC tissues by immunohistochemistry. The results indicated that macrophage polarization was found in metastases with the number of M1 macrophages (CD86+) decreased and M2 (CD163+) increased, though PD-L1 expression did not have a significant alteration. Compared to primary tumors, E-cadherin was significantly lower, while snail was higher, while no difference was found with N-cadherin and ZEB1. Correlation analysis indicated that snail, but not ZEB1, E-cadherin, or N-cadherin, was highly correlated with macrophage polarization. To conclude, the number of CD86+ M1 macrophages was increased while CD163+ M2 macrophages decreased in metastases, with no significant alteration of PD-L1 expression compared to primary tumors. EMT markers—Snail and E-cadherin—but not ZEB1 or N-cadherin, were found to be higher/lower in metastases, which mean that EMT played an important role in PDAC metastasis. Further analysis indicated that snail was highly correlated with M1 to M2 macrophage polarization, which prompted that EMT may be one reason for macrophage polarization induced TME alteration in PDAC metastasis.

The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.

Elevated de novo lipogenesis is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. Herein, we identify ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) through K48-linked deubiquitination, and in turn, this stabilization increases acetyl-CoA carboxylase (ACC) and ATP citrate lyase (ACLY) expressions. In addition, we find that USP22 promotes de novo fatty acid synthesis and contributes to HCC tumorigenesis, however, this tumorigenicity is suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vivo tumorigenesis experiments. In HCC, high expression of USP22 positively correlates with PPARγ, ACLY or ACC expression, and associates with a poor prognosis. Taken together, we identify a USP22-regulated lipogenesis mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Abstract Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of extracellular vesicles derived from CAFs on the liver metastasis of PDACs cells is not well characterized. The aim of this study was to determine whether specific derived from CAFs might be involved in liver metastasis in PDACs. We found that CAFs are intrinsically related with liver metastasis and thus the potential role of CAFs in PDACs was highlighted. Further, CAFs significantly increase the release of extracellular vesicles wit A and it caused increased liver metastasis. Advanced experiments demonstrated that, C, in recipient epithelial cells and promote proliferation, was up-regulated by A in EVs from CAFs. Besides, treatment of an inhibitor of A as well as an inhibitor of exosome release, GW4869, significantly reduces the activation of B, thus decreased the activity of C. Collectively, these findings show the potential for exosome inhibitors as treatment options for overcoming PDAC liver metastasis.

目的 总结临床药师参与1例胰腺癌伴糖尿病患者胰十二指肠切除术后治疗的药学实践.方法 临床药师协助临床医师选择糖尿病患者胰十二指肠切除术后治疗药物,为患者提供合理治疗方案.结果 患者术后感染症状体征明显好转,达到满意的治疗效果.结论 临床药师参与临床治疗实践,规范围术期抗菌药物的选择,提高了胰腺癌合并糖尿病患者术后继发腹腔感染的药物治疗水平.

Objective: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. Method: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. Results: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). Conclusion: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.

Objective:To construct a prognosis associated micro RNA(miRNA) prediction model based on bioinformatics analysis and evaluate its application value in pancreatic cancer patients.Methods:The retrospective cohort study was conducted. The clinicopathological data of 171 pancreatic cancer patients from the Cancer Genome Atlas (TCGA) (https: //cancergenome.nih.gov/) between establishment of database and September 2017 were collected. There were 93 males and 78 females, aged from 35 to 88 years, with a median age of 65 years. Of the 171 patients, 64 had complete clinicopathological data. Patients were allocated into training dataset consisting of 123 patients and validation dataset consisting of 48 patients using the random sampling method, with a ratio of 7∶3. The training dataset was used to construct a prediction model, and the validation dataset was used to evaluate performance of the prediction model. Nine pairs of miRNA sequencing data (GSE41372) of pancreatic cancer and adjacent tissues were downloaded from Gene Expression Omnibus database. The candidate miRNAs were selected from differentially expressed miRNAs in pancreatic cancer and adjacent tissues for LASSO-COX regression analysis based on the patients of training dataset. A prognosis associated miRNA prediction model was constructed upon survival associated miRNAs which were selected from candidate differentially expressed miRNAs. The performance of prognosis associated miRNA prediction model was validated in training dataset and validation dataset, the accuracy of model was evaluated using the area under curve (AUC) of the receiver operating characteristic curves and the efficiency was evaluated using the consistency index (C-index). Observation indicarors: (1) survival of patients; (2) screening results of differentially expressed miRNAs; (3) construction of prognosis associated miRNA model; (4) validation of prognosis associated miRNA model; (5) comparison of clinicopathological factors in pancreatic cancer patients; (6) analysis of factors for prognosis of pancreatic cancer patients; (7) comparison of prediction performance between prognosis associated miRNA model and the eighth edition TNM staging. Measurement data with normal distribution were represented as Mean± SD, comparison between groups was analyzed by the student- t test, and comparison between multiple groups was analyzed by the AVONA. Measurement data with skewed data were represented as M (range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Ordinal data were analyzed using the rank sum test. Correlation analysis was conducted based on count data to mine the correlation between prognosis associated miRNA model and clinicopathological factors. COX univariate analysis and multivariate analysis were applied to evaluate correlation with the results described as hazard ratio ( HR) and 95% confidence interval ( CI). HR<1 indicated the factor as a protective factor, HR>1 indicated the factor as a risk factor, and HR equal to 1 indicated no influence on survival. The Kaplan-Meier method was used to draw survival curve and calculate survival rates, and the Log-rank test was used for survival analysis. Results:(1) Survival of patients: 123 patients in the training dataset were followed up for 31-2 141 days, with a median follow-up time of 449 days. The 3- and 5-year survival rates were 16.67% and 8.06%. Forty-eight patients in the validation dataset were followed up for 41-2 182 days, with a median follow-up time of 457 days. The 3- and 5-year survival rates were 15.63% and 9.68%. There was no significant difference in the 3- or 5-year survival rates between the two groups ( χ2=0.017, 0.068, P>0.05). (2) Screening results of differentially expressed miRNAs. Results of bioinformatics analysis showed that 102 candidate differentially expressed miRNAs were selected, of which 63 were up-regulated in tumor tissues while 39 were down-regulated. (3) Construction of prognosis associated miRNA model: of the 102 candidate differentially expressed miRNAs, 5 survival associated miRNAs were selected, including miR-21, miR-125a-5p, miR-744, miR-374b, miR-664. The differential expression patterns of pancreatic cancer to adjacent tissues were up-regulation, up-regulation, down-regulation, up-regulation, and down-regulation, respectively, with the fold change of 4.00, 3.43, 3.85, 2.62, and 2.35. A prognostic expression equation constructed based on 5 survival associated miRNAs = 0.454×miR-21 expression level-0.492×miR-125a-5p expression level-0.49×miR-744 expression level-0.419×miR-374b expression level-0.036×miR-664 expression level. (4) Validation of prognosis associated miRNA model: The C-index of prognosis associated miRNA model was 0.643 and 0.642 for the training dataset and validation dataset, respectively. (5) Comparison of clinicopathological factors in pancreatic cancer patients: results of COX analysis showed that the prognosis associated miRNA model was highly related with pathological T stage and location of pancreatic cancer ( Z=45.481, χ2=10.176, P<0.05). (6) Analysis of factors for prognosis of pancreatic cancer patients: results of univariate analysis showed that pathological N stage, radiotherapy, molecular targeted therapy, score of prognosis associated miRNA model were related factors for prognosis pf pancreatic cancer patients ( HR=2.471, 0.290, 0.172, 2.001, 95% CI: 1.012-6.032, 0.101-0.833, 0.082-0.364, 1.371-2.922, P<0.05). Results of multivariate analysis showed that molecular targeted therapy was an independent protective factor for prognosis of pancreatic cancer patients ( HR=0.261, 95% CI: 0.116-0.588, P<0.05) and score of prognosis associated miRNA model≥1.16 was an independent risk factor for prognosis of pancreatic cancer patients ( HR=1.608, 95% CI: 1.091-2.369, P<0.05). (7) Comparison of prediction performance between prognosis associated miRNA model and the eighth edition TNM staging: in the training dataset, there was a significant difference in the prediction probability for 3- and 5-year survival of pancreatic cancer patients between prognosis associated miRNA model and the eighth edition TNM staging ( Z=-1.671, -1.867, P<0.05). The AUC of the prognosis associated miRNA model and the eight edition TNM staging for 3- and 5-year survival prediction was 0.797, 0.935 and 0.737 , 0.703, with the 95% CI of 0.622-0.972, 0.828-1.042 and 0.571-0.904 , 0.456-0.951. The C-index was 0.643 and 0.534. In the validation dataset, there was a significant difference in the prediction probability for 3- and 5-year survival of pancreatic cancer patients between prognosis associated miRNA model and the eighth edition TNM staging ( Z=-1.729, -1.923, P<0.05). The AUC of the prognosis associated miRNA model and the eight edition TNM staging was 0.750, 0.873 and 0.721 , 0.703, with the 95% CI of 0.553-0.948, 0.720-1.025 and 0.553-0.889, 0.456-0.950, respectively. The C-index was 0.642 and 0.544. Conclusions:A prognosis associated miRNA prediction model can be constructed based on 5 survival associated miRNAs in pancreatic cancer patients, as a complementation to current TNM staging and other clinicopathological parameters, which provides individual and accurate prediction of survival for reference in the clinical treatment.

Pancreatic cancer remains a lethal type of cancer with poor prognosis. Molecular classification enables in-depth, precise prognostic assessment. This study is aimed at identifying a robust and simple mRNA signature to predict the overall survival (OS) of pancreatic cancer (PC) patients. Differentially expressed genes (DEGs) between 45 paired pancreatic tumor samples and adjacent healthy tissues were selected. For risk determination, a LASSO Cox regression model with DEGs was used to generate the OS-associated risk score formula for the training cohort containing 177 PC patients. Another five independent datasets were used as the testing cohort to determine the predictive efficiency for further validation. In total, 441 DEGs were selected after considering the enrichment of classical pathways, such as EMT, cell cycle, cell adhesion, and PI3K-AKT. A five-gene signature for risk discrimination was established with high efficacy using LASSO Cox regression in the training group. External validation showed that patients identified by the gene expression signature to be in the high-risk group had poorer prognosis compared with the low-risk patients. Further investigation identified the differential epigenetic modification patterns of the five genes, which indicated their roles in tumor progression and their effect on therapy. In conclusion, we constructed a robust five-gene expression signature that could predict the OS of PC patients, offering a new insight for risk discrimination in daily clinical practice.

目的 探讨胰腺癌微环境下趋化因子C-X-C配体5(CXCL5)的表达及其与患者不良预后的关系.方法 应用免疫组化检测38例胰腺癌组织标本中CXCL5的表达;应用ELISA检测正常胰腺导管上皮细胞系HPDE6-C7及胰腺癌细胞系AsPC-1,PANC-1,BxPC-3上清液中CXCL5的表达;分析CXCL5表达与胰腺癌患者临床病理资料及总生存率的相关性;采用BxPC-3细胞上清液(BxCM)体外模拟胰腺癌微环境,流式细胞仪、ELISA及细胞毒性T淋巴细胞(CTL)杀伤实验评价肿瘤微环境下CXCL5对树突状细胞(DC)免疫功能的影响.结果 CXCL5在胰腺癌组织中表达量显著高于对应癌旁组织(4.448 vs.1.910,P<0.05),在各胰腺癌细胞系上清液中表达量也均明显高于HPDE6-C7细胞(均P<0.05);CXCL5表达量与胰腺癌的TNM分期、血管侵犯有关(均P<0.05);CXCL5高表达胰腺癌患者的总生存率明显低于低表达者(5.263％vs.26.316％,P<0.05);下调CXCL5能够显著降低BxCM对DC的抑制(均P<0.05).结论 CXCL5在胰腺癌中表达异常增高且与胰腺癌的T NM分期及不良预后密切相关,其机制可能与抑制DC的免疫功能有关.

Elevated de novo lipogenesis (DNL) is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. However, the molecular mechanism for its occurrence in HCC is still unclear. Herein, we identified ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with, deubiquitinates and stabilizes PPARγ through K48-linked deubiquitination, and in turn, this stabilization increases ACC and ACLY transcription. In addition, we found that USP22 promoted the de novo synthesis of fatty acid labeling from glucose tracers. USP22-dysregulated de novo fatty acid synthesis contributes to HCC progression, but USP22 was functionality suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vitro cell proliferation and in vivo tumorigenesis experiments. In HCC, USP22 expression positively correlates with PPARγ expression, and simultaneously, high expression of USP22 and PPARγ or USP22, ACC and ACLY is associated with a poor prognosis. Taken together, we identified a previously undescribed USP22-regulated lipogenesis molecular mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

目的 探讨肿瘤调控因子长链非编码RNA(lncRNA)PVT1对肝癌(HCC)细胞增殖与迁移能力的影响及机制.方法 通过TCGA数据库对HCC中PVT1的表达水平进行分析.采用瞬时转染技术构建PVT1敲低细胞系.通过CCK-8实验及划痕实验检测PVT1对HCC细胞增殖与迁移能力的影响.采用生物信息预测和荧光素酶实验验证PVT1与miR-17-5p的靶向结合情况.利用共转染实验验证PVT1能够通过miR-17-5p实现对HCC细胞增殖与迁移的调控.结果 PVT1在HCC组织和细胞中高表达.敲低PVT1后HCC细胞增殖与迁移能力显著降低.荧光素酶实验证实PVT1能够与miR-17-5p靶向结合,并且miR-17-5p介导了PVT1对HCC细胞增殖和迁移能力的调控作用.结论 ln-cRNA PVT1能够通过靶向抑制miR-17-5p从而促进HCC细胞的增殖和迁移.

BACKGROUND:Increasing evidence supports the association of microRNA with tumor occurrence and development. However, the expression of miR-6875-3p and its role in cell proliferation, invasion and metastasis in hepatocellular carcinoma (HCC) remains elusive.METHODS:The expression of miR-6875-3p and BTG2 in HCC tissues and cell lines was detected by using in situ hybridization, immunohistochemistry and qRT-PCR, respectively. A western blot assay, qRT-PCR and Luciferase reporter assay were employed to study the interaction between miR-6875-3p and BTG2. Cell proliferation invasion and metastasis were measured by MTT, transwell and matrigel analyses in vitro. In vivo, tumorigenicity and metastasis assays were performed in nude mice.RESULTS:We found that miR-6875-3p were elevated expressed in HCC tissues and cell lines, and negatively correlated with BTG2 expression, while positively correlated with tumor staging, size, degree of differentiation, and vascular invasion of HCC. Moreover, in vitro and in vivo assays showed that miR-6875-3p regulates EMT and improve the proliferation, metastasis and stem cell-like properties of HCC cells. BTG2 was identified as a direct and functional target of miR-6875-3p via the 3'-UTR of BTG2. We also confirmed that miR-6875-3p plays its biological functions via the BTG2/FAK/Akt pathway.CONCLUSION:Our study provides evidence that high expression of miR-6875-3p can promote tumorigenesis of HCC in vitro and in vivo, so as to function as a novel oncogene in HCC. In mechanism, we found that miR-6875-3p plays its biological functions via the BTG2/FAK/Akt pathway.

Dysregulation of deubiquitination pathway is associated with poor prognosis in cancers such as hepatocellular carcinoma (HCC). The mammalian target of rapamycin, mTOR, has become an attractive cancer therapeutic target in HCC. However, whether and how aberrant expression of deubiquitination pathway regulates mTOR pathway has remained elusive. Here we report that ubiquitin-specific protease 10 (USP10) functions as a tumor suppressor which inhibits mTOR pathway by stabilizing PTEN and AMPKα in HCC cells. Mechanistically, USP10 interacts and stabilizes PTEN and AMPKα by inhibiting their polyubiquitylation. This stabilization in turn inhibits AKT phosphorylation and mTOR Complex1 (mTORC1) activation. In human liver cancer, USP10 expression is downregulated in HCC tumor tissues across three independent HCC cohorts, and lower-expression of USP10 will generate poor prognosis outcome. Collectively, our results uncover an undescribed mechanism where USP10, as a tumor suppressor, negatively regulates mTORC1 activation and AKT phosphorylation by stabilizing AMPKα and PTEN in HCC cells. This study sheds light on the theoretical basis of mTOR signaling pathway-oriented targeting treatment in clinic.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer, and the majority of patients with HCC are deprived of effective curative methods. Osthole is a Chinese herbal medicine which has been reported to possess various pharmacological functions, including hepatocellular protection. In the present study, we investigated the anticancer activity of osthole using HCC cell lines. We found that osthole inhibited HCC cell proliferation, induced cell cycle arrest, triggered DNA damage and suppressed migration in HCC cell lines. Furthermore, we demonstrated that osthole not only contributed to cell cycle G2/M phase arrest via downregulation of Cdc2 and cyclin B1 levels, but also induced DNA damage via an increase in ERCC1 expression. In addition, osthole inhibited the migration of HCC cell lines by significantly downregulating MMP-2 and MMP-9 levels. Finally, we demonstrated that osthole inhibited epithelial-mesenchymal transition (EMT) via increasing the expression of epithelial biomarkers E-cadherin and β-catenin, and significantly decreasing mesenchymal N-cadherin and vimentin protein expression. These results suggest that osthole may have potential chemotherapeutic activity against HCC.

Cholangiocarcinoma (CCA) is a very heterogeneous group of neoplasms,for which the early diagnosis is difficult,present treatment methods are inadequate and the treatment effects are also limited.Thus,a detailed knowledge of the molecular pathological profiles of CCA is important for improving its diagnosis,treatment and outcomes.With the development of molecular biological technologies,the molecular pathological mechanisms of CCA will gradually be revealed and clarified,which may provide new ideas and approaches for early diagnosis and targeted therapy of CCA.Here,the authors present the current research progress in molecular pathology of CCA,

The incidence of pancreatic neuroendocrine neoplasms is progressively growing.The clinical manifestation and treatment of this disease are complicated.Multi disciplinary combination therapy is needed to improve prognosis and life quality of patients.