Machine learning identifies risk factors associated with long-term opioid use in fibromyalgia patients newly initiated on an opioid.

OBJECTIVES: Fibromyalgia is frequently treated with opioids due to limited therapeutic options. Long-term opioid use is associated with several adverse outcomes. Identifying factors associated with long-term opioid use is the first step in developing targeted interventions. The aim of this study was to evaluate risk factors in fibromyalgia patients newly initiated on opioids using machine learning. METHODS: A retrospective cohort study was conducted using a nationally representative primary care dataset from the UK, from the Clinical Research Practice Datalink. Fibromyalgia patients without prior cancer who were new opioid users were included. Logistic regression, a random forest model and Boruta feature selection were used to identify risk factors related to long-term opioid use. Adjusted ORs (aORs) and feature importance scores were calculated to gauge the strength of these associations. RESULTS: In this study, 28 552 fibromyalgia patients initiating opioids were identified of which 7369 patients (26%) had long-term opioid use. High initial opioid dose (aOR: 31.96, mean decrease accuracy (MDA) 135), history of self-harm (aOR: 2.01, MDA 44), obesity (aOR: 2.43, MDA 36), high deprivation (aOR: 2.00, MDA 31) and substance use disorder (aOR: 2.08, MDA 25) were the factors most strongly associated with long-term use. CONCLUSIONS: High dose of initial opioid prescription, a history of self-harm, obesity, high deprivation, substance use disorder and age were associated with long-term opioid use. This study underscores the importance of recognising these individual risk factors in fibromyalgia patients to better navigate the complexities of opioid use and facilitate patient-centred care.

Research on sustainable collaborative scheduling problem of multi-stage mixed flow shop for crankshaft components.

The crankshaft manufacturing process primarily comprises machining, single jacket, and double jacket stages. These stages collectively produce substantial carbon emissions, which significantly impact the environment. Low-carbon energy development and humanity's future are closely related. To promote the sustainable development of crankshaft manufacturing enterprises and improve the production efficiency of crankshafts, research on sustainable collaborative scheduling problems in multi-stage mixed flow shop for crankshaft components is conducted. In addition, the transportation process of related workpieces in the crankshaft manufacturing process, which generally have a large mass, also produces substantial carbon emissions. This paper constructs a multi-objective integer optimization model based on the manufacturing process characteristics of crankshaft components, with minimizing the maximum manufacturing time and carbon emissions as optimization objectives. Considering the complexity of the problem, a comprehensive algorithm integrating moth-flame optimization and NSGA-III is used to solve the mathematical model. Through case experiments, the integrated algorithm is compared and analysed with four classic multi-objective optimization algorithms: NSGA-III, NSGA-II, MOEA/D, and MOPSO. The experiments demonstrate that the algorithm presented in this paper offers significantly enhanced optimization efficiency in solving the problem under study compared to other algorithms. Moreover, this paper compares multi-stage collaborative scheduling and non-collaborative scheduling in the crankshaft manufacturing process, ultimately demonstrating that collaborative scheduling is more conducive to the sustainable development of manufacturing enterprises. The results indicate that the annual carbon emissions can reduce about 3.6 ton.

PRKRA promotes pancreatic cancer progression by upregulating MMP1 transcription via the NF-κB pathway.

Objective: Pancreatic cancer (PC) is highly malignant, but the underlying mechanisms of cancer progression remain unclear. PRKRA is involved in cellular stress response, but its role in PC was unknown. Methods: The expression of PRKRA between normal and tumor tissues were compared, and the prognostic value of PRKRA was evaluated. SiRNA and plasmids were applied to investigate the effects of PRKRA on PC cells. Organoids and cell lines with knockout and overexpression of PRKRA were established by CRISPR/Cas9 and lentivirus. The effects of PRKRA on PC were evaluated in vivo by cell-derived xenografts. The downstream genes of PRKRA were screened by transcriptome sequencing. The regulation of the target gene was validated by RT-qPCR, western blot, ChIP and dual luciferase reporter assay. Besides, the correlation between PRKRA and gemcitabine sensitivity was investigated by PC organoids. Results: PRKRA was significantly overexpressed in PC tissues and independently associated with poor prognosis. PRKRA promoted the proliferation, migration, and chemoresistance of PC cells. The proliferation of PC organoids was decreased by PRKRA knockout. The growth and chemoresistance of xenografts were increased by PRKRA overexpression. Mechanistically, PRKRA upregulated the transcription of MMP1 via NF-κB pathway. ChIP and dual luciferase reporter assay showed that NF-κB subunit P65 could bind to the promoter of MMP1. The sensitivity of PC organoids to gemcitabine was negatively correlated with the expression of PRKRA and MMP1. Conclusions: Our study indicated that the PRKRA/NF-κB/MMP1 axis promoted the progression of PC and may serve as a potential therapeutic target and prognosis marker.

mTOR inhibitor, gemcitabine and PD-L1 antibody blockade combination therapy suppresses pancreatic cancer progression via metabolic reprogramming and immune microenvironment remodeling in Trp53flox/+LSL-KrasG12D/+Pdx-1-Cre murine models.

OBJECTIVE: Resistance to immunotherapy and chemotherapy hinders the prognosis of pancreatic cancer(PC). We hypothesized that the combination of mTOR inhibitor sirolimus and gemcitabine would change the metabolic landscape of PC and enhance the anti-PD-L1 therapy. METHODS: In KPC mice, the following regimens were administered and tumor growth inhibition rates(TGI%) were calculated: sirolimus(S), PD-L1 antibody(P), gemcitabine(G), sirolimus + PD-L1 antibody(SP), sirolimus + gemcitabine(SG), PD-L1 + gemcitabine(PG) and sirolimus + PD-L1 antibody + gemcitabine(SPG). The metabolic changes of tumors were identified by LC-MS and subpopulations of immune cells were measured by flow cytometry. Sirolimus treated macrophages were co-cultured with PC cells in vitro, and the metabolic changes of macrophages and tumor cells as well as tumor cells' viability were detected. RESULTS: The monotherapy of S, P and G didn't inhibit tumor growth significantly. The combination of SP, PG and SG didn't improve the TGI% significantly compared with monotherapy. However, the TGI% of SPG combination was higher than other groups. The proportion of CD68+ macrophages increased in the peripheral blood and CD8+ T cells decreased in the tumor tissues after SPG treatment. LC-MS identified 42 differential metabolites caused by sirolimus in SPG group, among which 10 metabolites had potential effects on macrophages. Sirolimus treated M1 and M2 macrophages inhibited the proliferation of tumor cells and decreased tumor cells' glycolysis. The glycolysis of M2 macrophages was increased by sirolimus. CONCLUSIONS: mTOR inhibitor can change the immune microenvironment of PC via metabolic reprogramming, thus promoting the efficacy of PD-L1 blockade when combined with gemcitabine.

Characteristics of lymph node stations/basins metastasis and construction and validation of a preoperative combination prediction model that accurately excludes lymph node metastasis in early gastric cancer.

Objective: To explore the candidate indications for function-preserving curative gastrectomy and sentinel lymph node navigation surgery in early gastric cancer (EGC). Methods: The clinicopathological data of 561 patients with EGC who underwent radical gastrectomy for gastric cancer at Peking University Cancer Hospital from November 2010 to November 2020 with postoperative pathological stage pT1 and complete examination data, were collected. Pearson's Chi-square test was used and binary logistic regression was employed for univariate and multivariate analyses. Combined analysis of multiple risk and protective factors for lymph node metastasis (LNM) of EGC was performed. A negative predictive value (NPV) combination model was built and validated. Results: LNM occurred in 85 of 561 patients with EGC, and the LNM rate was 15.15%. NPV for LNM reached 100% based on three characteristics, including ulcer-free, moderately well differentiation and patient <65 years old or tumor located at the proximal 1/3 of the stomach. Regarding lymphatic basin metastasis, multivariate analysis showed that the metastatic proportion of the left gastric artery lymphatic basin was significantly higher in male patients compared with female patients (65.96% vs. 38.89%, P<0.05). The proportion of right gastroepiploic artery lymphatic basin metastasis in patients with a maximum tumor diameter >2 cm was significantly greater than that noted in patients with a maximum tumor diameter ≤2 cm (60.78% vs. 28.13%, P<0.05). Conclusions: Characteristics of lymph node stations/basins metastasis will facilitate precise lymph node resection. The NPV for LNM reaches 100% based on the following two conditions: young and middle-aged EGC patients, well-differentiated tumors, and without ulcers; or well-differentiated tumors, without ulcers, and tumors located in the proximal stomach. These findings can be used as the recommended indications for function-preserving curative gastrectomy and sentinel lymph node navigation surgery.

Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models.

PURPOSE: Gemcitabine is most commonly used for pancreatic cancer. However, the molecular features and mechanisms of the frequently occurring resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment. EXPERIMENTAL DESIGN: In this study, we established 66 patient-derived xenografts (PDXs) on the basis of clinical pancreatic cancer specimens and treated them with gemcitabine. We generated multiomics data (including whole-exome sequencing, RNA sequencing, miRNA sequencing, and DNA methylation array) of 15 drug-sensitive and 13 -resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and acquired resistance. Then, short hairpin RNA-based high-content screening was implemented to validate the function of the deregulated genes. RESULTS: The comprehensive multiomics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in pancreatic cancer cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of patients with pancreatic cancer and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, and hypoxia-inducible factor-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance. CONCLUSIONS: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in pancreatic cancer and provides potential therapy targets for overcoming gemcitabine resistance.

Carboxypeptidase E down-regulation regulates transcriptional and epigenetic profiles in pancreatic cancer cell line: A network analysis.

BACKGROUND: Pancreatic cancer is a malignant tumor and its incidence has increased in recent years. Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme that has been shown to be associated with tumor growth and invasion in various cancers including pancreatic cancer. OBJECTIVE: To understand the molecular mechanism underlying the proliferative effects of CPE in cancer cells. METHODS: We down-regulated CPE gene expression in PANC-1 cell, a pancreatic cell line, and investigated mRNA, miRNA, circRNA and lncRNA expression profiling in PANC-1 cells from control group and CPE knock-down group by microarray analysis. We further validated the top 14 differentially expressed circRNAs by qRT-PCR. RESULTS: Our results showed that CPE down-regulation caused decreased cell proliferation. The microarray data showed 107, 15, 299 and 360 differentially expressed mRNAs, miRNAs, circRNAs, and lncRNAs, respectively between control group and CPE knock-down group. Of Which, 41 mRNAs, 12 miRNAs, 133 circRNAs, and 262 lncRNAs were down-regulated; 66 mRNAs, 3 miRNAs, 166 circRNAs, and 98 lncRNAs were up-regulated. Bioinformatics analysis showed that the top significantly enriched pathways for the differentially expressed RNAs were related to cancer onset and/or progression, these included p53 signaling pathway, ECM-receptor interaction, focal adhesion and Wnt signaling pathway. We further performed network analysis to assess the mRNA, miRNA, circRNA and lncRNA correlations, and showed that HUWE1, hsa-miR-6780b-5p, has_circ_0058208 and lnc-G3BP1-3:8 were in the core position of the network. CONCLUSIONS: Taken together, these results identified potential CPE regulated core genes and pathways for cell proliferation in pancreatic cancer cell, and therefore provide potential targets for the treatment of pancreatic cancer.

Expression, function and clinical application of stanniocalcin-1 in cancer.

The glycoprotein stanniocalcin-1 functions as a regulatory endocrine hormone that maintains the balance of calcium and phosphorus in bony fish and as a paracrine/autocrine factor involved in many physiological/pathological processes in humans, including carcinogenesis. In this review, we provide an overview of (a) the possible mechanisms through which STC1 affects the malignant properties of cancer, (b) transcriptional and post-transcriptional regulation pathways of STC1 and (c) the potential clinical relevance of STC1 as a cancer biomarker and even a therapeutic target in the future. Exploring the role of STC1 in cancer development may provide a better understanding of the tumorigenesis process in humans and may facilitate finding an effective therapeutic method against cancer.

Mechanistic target of rapamycin in the tumor microenvironment and its potential as a therapeutic target for pancreatic cancer.

Pancreatic cancer(PC) is a devastating disease with a poor prognosis; however, few treatment options are available and the search continues for feasible molecular therapeutic targets, both in the tumor itself and in the tumor microenvironment. The mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive target due to its regulatory role in multiple cellular processes, including metabolism, proliferation, survival, and differentiation, under physiological and pathological conditions. Although mTOR-regulated events in tumor cells and the tumor microenvironment are known to restrict the development and growth of tumor cells, monotherapy with mTOR inhibitors has shown limited efficacy against PC to date, suggesting the need for alternative approaches. In this review, we describe the mechanisms by which mTOR modulates the PC microenvironment and suggest ways its function in immune cells might be exploited for the treatment of PC. We also discuss preclinical and clinical studies with mTOR inhibitors in combination with other therapeutic strategies, most notably immunotherapy. Finally, we highlight the promise that mTOR combinatorial therapy may hold for the treatment of PC in the near future.

OLR1 Promotes Pancreatic Cancer Metastasis via Increased c-Myc Expression and Transcription of HMGA2.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, the mechanisms of metastasis in pancreatic cancer remain unclear. Oxidized low-density lipoprotein receptor 1 (OLR1), a lectin-like scavenger receptor that recognizes several ligands, such as oxidized low-density lipoprotein, was previously reported in cardiovascular and metabolic diseases. The role and mechanism of OLR1 in pancreatic cancer is unclear. In this study, we found that OLR1 expression was significantly higher in pancreatic cancer tissues than that in adjacent normal tissues and closely associated with reduced overall survival. OLR1 promoted proliferation and metastasis of pancreatic cancer cells in vitro and in vivo. Mechanistically, OLR1 increased HMGA2 transcription by upregulating c-Myc expression to promote the metastasis of pancreatic cancer cells. In addition, patients with pancreatic cancer with high expression of OLR1-c-Myc-HMGA2 axis showed worse prognosis compared with patients with low expression of OLR1-c-Myc-HMGA2 axis. IMPLICATIONS: Our findings suggested that the OLR1-c-Myc-HMGA2 axis promotes metastasis of pancreatic cancer cells and may serve as potential therapeutic targets and prognosis markers for patients with pancreatic cancer.

Role of the microbiome in occurrence, development and treatment of pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies. Recent studies indicated that development of pancreatic cancer may be intimately connected with the microbiome. In this review, we discuss the mechanisms through which microbiomes affect the development of pancreatic cancer, including inflammation and immunomodulation. Potential therapeutic and diagnostic applications of microbiomes are also discussed. For example, microbiomes may serve as diagnostic markers for pancreatic cancer, and may also play an important role in determining the efficacies of treatments such as chemo- and immunotherapies. Future studies will provide additional insights into the various roles of microbiomes in pancreatic cancer.

[Qualitative identification of impurities and principal component quantitative analysis of zearalanone on purity certified reference material].

A liquid chromatography method was established for the determination of zearalanone (ZAN) raw material. The qualitative analysis of ZAN and its trace impurities was performed by ultra performance liquid chromatography-diode array detector (UPLC-DAD) and ultra performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS), and the response factors of each impurity were calculated. The three main organic impurities in the ZAN raw material were identified as ß -zearalanol, α -zearalanol and a dehydration product of zearalanol with relative response factors of 0.5352, 0.8594 and 0.6973, respectively. The main component of the ZAN raw material was determined by the calibration factor normalization method. The purity of zearalanone was determined to be 99.6% with a standard deviation of 0.01%. This method can provide a technical support for the development of ZAN standard materials.

Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer.

BACKGROUND: Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. METHODS: Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. RESULTS: Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. CONCLUSION: Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

Novel discoveries targeting gemcitabine-based chemoresistance and new therapies in pancreatic cancer: How far are we from the destination?

Pancreatic cancer (PC) remains one of the deadliest malignancies worldwide. Chemoresistance is a significant clinical problem in pancreatic ductal adenocarcinoma (PDAC) and numerous potential mechanisms have been demonstrated but much remains to be understood. To overcome the existing limitations in PC treatment, newer approaches targeting intrinsic or acquired mechanisms have been found to improve drug therapeutic effectiveness in PC patients. Here, we provide an update of the most recent findings and their implications for clinicians, and attempt to summarize the various aspects of different individualized novel therapies for PC that could most benefit metastatic PDAC patients.

Integrated analysis of gene expression and methylation profiles of novel pancreatic cancer cell lines with highly metastatic activity.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, highly metastatic human pancreatic cancer cell lines suitable for studies of metastasis are currently lacking. Here we established two highly metastatic human pancreatic cancer cell lines, MIA PaCa-2 In8 and Panc-1 In8, by Matrigel induction assay. The cell lines were further characterized both in vitro and in vivo. MIA PaCa-2 In8 and Panc-1 In8 cells demonstrated increased migration and invasion compared with their respective parental cells. Following injection into nude mice, MIA PaCa-2 In8 and Panc-1 In8 cells resulted in more pulmonary metastases compared with the parental cells. Furthermore, analyses of mRNA, long non-coding RNA, micro RNA, and methylation profiling revealed that these factors were aberrantly regulated in the highly metastatic cells, indicating that they probably affected metastasis. We thus established and characterized two highly metastatic human pancreatic cell lines that could be used as valuable tools for future investigations into the pathogenesis, metastasis, and potential treatment of human pancreatic cancer.

Pancreatic head cancer: Open or minimally invasive pancreaticoduodenectomy?

Pancreatic head cancer still represents an insurmountable barrier for patients and pancreatic surgeons. Pancreaticoduodenectomy (PD) continues to be the operative standard of care and potentially curative procedure for pancreatic head cancer. Despite the rapid development of minimally invasive techniques, whether the efficacy of minimally invasive pancreaticoduodenectomy (MIPD) is noninferior or superior to open pancreaticoduodenectomy (OPD) remains unclear. In this review, we summarized the history of OPD and MIPD and the latest staging and classification information for pancreatic head cancer as well as the proposed recommendations for MIPD indications for patients with pancreatic head cancer. By reviewing the MIPD- vs. OPD-related literature, we found that MIPD shows noninferiority or superiority to OPD in terms of safety, feasibility, enhanced recovery after surgery (ERAS) and several short-term and long-term outcomes. In addition, we analyzed and summarized the different MIPD outcomes in the USA, Europe and China. Certain debates over MIPD have continued, however, selection bias, the large number of low-volume centers, the steep MIPD learning curve, high conversion rate and administration of neoadjuvant therapy may limit the application of MIPD for pancreatic head cancer.

LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.

BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive. METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer. CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

Tumor microenvironment participates in metastasis of pancreatic cancer.

Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial-mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival.

MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.

BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.