Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing.

Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care.

Long-term quality of life between duodenum-preserving pancreatic head resection and pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: The authors aimed to compare the differences in quality of life (QOL) and overall survival (OS) between duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD) during long-term follow-up. DPPHR and PD have been shown to be effective in alleviating symptoms and controlling malignancies, but there is ongoing debate over whether DPPHR has an advantage over PD in terms of long-term benefits. METHOD: The authors searched the PubMed, Cochrane, Embase, and Web of Science databases for relevant studies comparing DPPHR and PD published before 1 May 2023. This study was registered with PROSPERO. Randomised controlled trials and non-randomised studies were included. The Mantel-Haenszel model and inverse variance method were used as statistical approaches for data synthesis. Subgroup analyses were conducted to evaluate the heterogeneity of the results. The primary outcome was the global QOL score, measured using the QLQ-C30 system. RESULTS: The authors analysed ten studies involving 976 patients (456 DPPHR and 520 PD). The global QOL score did not differ significantly between the DPPHR and PD groups [standard mean difference (SMD) 0.21, 95% CI (-0.05, 0.46), P =0.109, I2 =70%]; however, the OS time of patients with DPPHR was significantly improved [hazard ratio 0.59, 95% CI (0.44, 0.77), P <0.001, I2 =0%]. The follow-up length may be an important source of heterogeneity. Studies with follow-up length between two to seven years showed better global QOL for DPPHR than for PD [SMD 0.43, 95% CI (0.23, 0.64), P <0.001, I2 =0%]. There were no significant differences between the two groups in any of the functional scales of the QLQ-C30 system (all P >0.05). On the symptom scale, patients in the DPPHR group had lower scores for fatigue, nausea and vomiting, loss of appetite, insomnia, and diarrhoea than those in the PD group (all P <0.05). CONCLUSIONS: There were no significant differences in global QOL scores between the two surgeries; however, DPPHR had advantages over PD in terms of safer perioperative outcomes, lower long-term symptom scores, and longer OS times. Therefore, DPPHR should be recommended over PD for the treatment of benign pancreatic diseases and low-grade malignant tumours.

An E3 ubiquitin-proteasome gene signature for predicting prognosis in patients with pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, which is demonstrated with remarkable resistance to radiotherapy and chemotherapy. The identification of prognosis signature and novel prognostic markers will facilitate patient stratification and an individualized precision therapy strategy. In this study, TCGA-PAAD was used to screen prognostic E3 ubiquitin ligases and establish prognostic signatures, and GEO database was used to verify the accuracy of prognostic signatures. Functional analysis, in vitro experiments and clinical cohort studies were used to analyze the function and prognostic efficacy of the target gene. An E3 ligase-based signature of 9 genes and the nomogram were developed, and the signature was proved to accurately predict the prognosis of patients with pancreatic cancer. WDR37 might be the most prognostic E3 ubiquitin ligase in pancreatic cancer, and the clinical cohort analyses suggested a tumor-suppressive role. The results of functional analysis and in vitro experiments indicated that WDR37 may promote the degradation of TCP1 complex to inhibit tumor and improve immune cell infiltration. The E3 ligase-based signature accurately predicted the prognosis of patients with pancreatic cancer, so it can be used as a decision-making tool to guide the treatment of patients with pancreatic cancer. At the same time, WDR37, the main gene in E3PMP signature, can be used as the most prognostic E3 ubiquitin ligase in the treatment of pancreatic cancer.

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition.

BACKGROUND: Epidermal growth factor receptor (EGFR) is an essential target for cancer treatment. However, EGFR inhibitor erlotinib showed limited clinical benefit in pancreatic cancer therapy. Here, we showed the underlying mechanism of tumor microenvironment suppressing the sensitivity of EGFR inhibitor through the pancreatic stellate cell (PSC). METHODS: The expression of alpha-smooth muscle actin (α-SMA) and hypoxia marker in human pancreatic cancer tissues were detected by immunohistochemistry, and their correlation with overall survival was evaluated. Human immortalized PSC was constructed and used to investigate the potential effect on pancreatic cancer cell lines in hypoxia and normoxia. Luciferase reporter assay and Chromatin immunoprecipitation were performed to explore the potential mechanisms in vitro. The combined inhibition of EGFR and Met was evaluated in an orthotopic xenograft mouse model of pancreatic cancer. FINDINGS: We found that high expression levels of α-SMA and hypoxia markers are associated with poor prognosis of pancreatic cancer patients. Mechanistically, we demonstrated that hypoxia induced the expression and secretion of HGF in PSC via transcription factor HIF-1α. PSC-derived HGF activates Met, the HGF receptor, suppressing the sensitivity of pancreatic cancer cells to EGFR inhibitor in a KRAS-independent manner by activating the PI3K-AKT pathway. Furthermore, we found that the combination of EGFR inhibitor and Met inhibitor significantly suppressed tumor growth in an orthotopic xenograft mouse model. INTERPRETATION: Our study revealed a previously uncharacterized HIF1α-HGF-Met-PI3K-AKT signaling axis between PSC and cancer cells and indicated that EGFR inhibition plus Met inhibition might be a promising strategy for pancreatic cancer treatment. FUNDING: This study was supported by The National Natural Science Foundation of China.

LncRNA FAM83H-AS1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing FAM83H mRNA to protect ß-catenin from degradation.

BACKGROUND: Pancreatic ductal adenocarcinoma is prone to metastasis, resulting in short survival and low quality of life. LncRNAs are pivotal orchestrators that participate in various tumor progress. The underlying role and mechanism of lncRNA FAM83H-AS1 is still unknown in PDAC progression. METHODS: To address this issue, firstly, we profiled and analyzed the aberrant lncRNA expression in TCGA database and identified FAM83H-AS1 as the most effective one in promoting the migration of pancreatic cancer cells. Then, the expression levels of FAM83H-AS1 in patient's serum, tumor tissues and PDAC cells were detected using RT-qPCR, and FAM83H-AS1 distribution in PDAC cells was determined by performing FISH and RT-qPCR. Next, a series of in vivo and in vitro functional assays were conducted to elucidate the role of FAM83H-AS1 in cell growth and metastasis in PDAC. The regulatory relationship between FAM83H-AS1 and FAM83H (the homologous gene of FAM83H-AS1) was verified by performing protein and RNA degradation assays respectively. Co-IP assays were performed to explore the potential regulatory mechanism of FAM83H to ß-catenin. Rescue assays were performed to validate the regulation of the FAM83H-AS1/FAM83H/ß-catenin axis in PDAC progression. RESULTS: FAM83H-AS1 was highly expressed in the tumor tissues and serum of patients with PDAC, and was correlated with shorter survival. FAM83H-AS1 significantly promoted the proliferation, invasion and metastasis of PDAC cells, by protecting FAM83H mRNA from degradation. Importantly, FAM83H protein manifested the similar malignant functions as that of FAM83H-AS1 in PDAC cells, and could bind to ß-catenin. Specifically, FAM83H could decrease the ubiquitylation of ß-catenin, and accordingly activated the effector genes of Wnt/ß-catenin signaling. CONCLUSIONS: Collectively, FAM83H-AS1 could promote FAM83H expression by stabilizing its mRNA, allowing FAM83H to decrease the ubiquitylation of ß-catenin, thus resulted in an amplified FAM83H-AS1/FAM83H/ß-catenin signal axis to promote PDAC progression. FAM83H-AS1 might be a novel prognostic and therapeutic target for combating PDAC.

Intracapsular approach used in laparoscopic duodenum-preserving total pancreatic head resection for pancreatic head benign or low-grade malignant tumors.

PURPOSE: Laparoscopic duodenum-preserving total pancreatic head resection (LDPPHRt) is used for treating benign or low-grade malignant tumors of the pancreatic head. However, preservation of the duodenum and biliary tract integrity remains challenging. We present a new approach for LDPPHRt and evaluate its feasibility and safety. METHODS: From April 2020 to December 2020, 30 patients successfully underwent LDPPHRt using the intracapsular approach in our center. Their medical records were reviewed for relevant clinical characteristics, pathologic findings, postoperative complications, and survival. RESULTS: The median diameter of the lesions was 3.6 cm (range, 2.0-5.5 cm). The median operative time was 234.7 min (range, 195-310 min). The median blood loss was 66.7 ml (range, 20-250 ml). The morbidity rate was 26.7%, including POPF, hemorrhage, lymphatic leakage, wound infection, pulmonary infection, and delayed gastric emptying. Five patients developed pancreatic fistula type A, and two patients had type B, classified according to the International Study Group on Pancreatic Fistula. No biliary tract injury or duodenal leakage was observed. The median postoperative hospital stay was 11.5 days (range, 6-25), and the operative mortality rate was 0%. CONCLUSION: The intracapsular approach is a feasible and safe surgical procedure in LDPPHRt for patients with benign or low-grade malignant tumors, especially those without severe pancreatic head fibrosis or peripancreatic adhesions.

Comparison of safety and effectiveness between laparoscopic and open pancreatoduodenectomy: A systematic review and meta-analysis.

BACKGROUND: Validity of the laparoscopic approach in pancreatic head lesion remains debatable. This study aims to compare the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD) and open pancreatoduodenectomy (OPD) and investigate the source of heterogeneity from surgeons' and patients' perspectives. METHOD: We searched PubMed, Cochrane, Embase, and Web of Science for studies published before February 1, 2021. Of 6578 articles, 81 were full-text reviewed. The primary outcome was mortality. Three independent reviewers screened and extracted the data and resolved disagreements by consensus. Studies were evaluated for quality using ROB2.0 and ROBINS-I. According to different study designs, sensitivity and meta-regression analyses were conducted to explore the heterogeneity source. This meta-analyses was also conducted to explore the learning curve's heterogeneity. This study was registered with PROSPERO, CRD42021234579. RESULTS: We analyzed 34 studies involving 46,729 patients (4705 LPD and 42,024 OPD). LPD was associated with lower (P = 0.025) in unmatched studies (P = 0.017). No differences in mortality existed in randomized controlled trials (P = 0.854) and matched studies (P = 0.726). Sensitivity analysis found no significant difference in mortality in elderly patients, patients with pancreatic cancer, and in high- and low-volume hospitals (all P > 0.05). In studies at the early period of LPD (<40 cases), higher mortality (P < 0.001) was found (all P < 0.05).LPD showed non-inferiority in length of stay, complications, and survival outcomes in all analyses. CONCLUSION: In high-volume centers with adequate surgical experience, LPD in selected patients appears to be a valid alternative to LPD with comparable mortality, LOS, complications, and survival outcomes.

Correction: LncRNA AFAP1-AS1 promotes growth and metastasis of cholangiocarcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.16880.].

Prognostic validity of the American joint committee on cancer eighth edition staging system for well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: The American Joint Committee on Cancer (AJCC) made improvements for staging pancreatic neuroendocrine tumors (pNETs) in its 8th Edition; however, multicenter studies were not included. METHODS: We collected multicenter datasets (n = 1,086, between 2004 and 2018) to validate the value of AJCC 8 and other coexisting staging systems through univariate and multivariate analysis for well-differentiated (G1/G2) pNETs. RESULTS: Compared to other coexisting staging systems, AJCC 7 only included 12 (1.1%) patients with stage III tumors. Patients with European Neuroendocrine Tumor Society (ENETS) stage IIB disease had a higher risk of death than patients with stage IIIA (hazard ratio [HR]: 4.376 vs. 4.322). For the modified ENETS staging system, patients with stage IIB disease had a higher risk of death than patients with stage III (HR: 6.078 vs. 5.341). According to AJCC 8, the proportions of patients with stage I, II, III, and IV were 25.7%, 40.3%, 23.6%, and 10.4%, respectively. As the stage advanced, the median survival time decreased (NA, 144.7, 100.8, 72.0 months, respectively), and the risk of death increased (HR: II = 3.145, III = 5.925, and IV = 8.762). CONCLUSION: These findings suggest that AJCC 8 had a more reasonable proportional distribution and the risk of death was better correlated with disease stage.

Circ_0092367 Inhibits EMT and Gemcitabine Resistance in Pancreatic Cancer via Regulating the miR-1206/ESRP1 Axis.

Gemcitabine is the first-line treatment for patients with pancreatic cancer (PC), yet most patients develop resistance to gemcitabine. Recent studies showed that circular RNAs (circRNAs) have important regulatory roles in PC progression and chemoresistance. In this study, the ability of circRNA circ_0092367 to enhance gemcitabine efficacy was tested and the underlying molecular mechanism of circ_0092367 was investigated. The expression levels of circ_0092367, miR-1206, and ESRP1 were measured using qRT-PCR experiments. The effects of circ_0092367, miR-1206, and ESRP1 on PC cell lines exposed to gemcitabine were examined by CCK-8 assays. We performed luciferase assays to determine the relationship between circ_0092367 and miR-1206 and between miR-1206 and ESRP1. We demonstrated that circ_0092367 was significantly downregulated in PC tissues and cell lines, and a high expression of circ_0092367 was associated with improved survival in patients with PC. Gain- and loss-of-function assays revealed that circ_0092367 inhibited epithelial-mesenchymal transition (EMT) phenotypes and sensitized PC cells to gemcitabine treatment in vitro and in vivo. Cytoplasmic circ_0092367 could directly repress the levels of miR-1206 and thus upregulate the expression of ESRP1, thereby inhibiting EMT and enhancing the sensitivity of PC cells to gemcitabine treatment. Our findings show that circ_0092367 plays a crucial role in sensitizing PC cells to gemcitabine by modulating the miR-1206/ESRP1 axis, highlighting its potential as a valuable therapeutic target in PC patients.

New staging classification for pancreatic neuroendocrine neoplasms combining TNM stage and WHO grade classification [].

AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.

MiR-146b-3p regulates proliferation of pancreatic cancer cells with stem cell-like properties by targeting MAP3K10.

Purpose: Cancer stem cells (CSCs) initiate and maintain tumorigenesis due to their unique pluripotency. However, pancreatic stem cell gene signatures are not completely revealed yet. Here, we isolated pancreatic cancer stem cells (P-CSCs) and exploited their distinct genome-wide mRNA and miRNA expression profiles using microarrays. Methods: CD24+ CD44+ ESA+ cells were isolated from two pancreatic xenograft cells by the flow cytometry and identified the stem cell-like properties by the tumor formation, self-renew and chemoresistance. Microarrays and qRT-PCR were used to exploit their distinct Genome-wide mRNA and miRNA expression profiles. The function and candidate target genes of key microRNA were detected after Ectopic restoration in the pancreatic cancer cell lines MIA Paca-2 (CSChigh) and BxPC-3 (CSClow). Results: In this study, we isolated P-CSCs from two xenografts cells. Genome-wide profiling experiments showed 479 genes and 15 microRNAs specifically expressed in the P-CSCs, including genes involved in TGF-ß and p53 signaling pathways and particularly miR-146b-3p as the most significantly downregulated miRNA. We confirmed miR-146b-3p as a downregulated signature in pancreatic cancer tissues and cell line MIA Paca-2 (CSChigh) cells. Ectopic restoration of miR-146b-3p expression with pre-miR reduced cell proliferation, induced apoptosis, increased G1 phase and reduced S phase in cell cycle in MIA Paca-2 (CSChigh), but not in BxPC-3 (CSClow). Re-expression of miR-146b-3p with lentivirus significantly inhibited tumorigenicity in vivo in MIA Paca-2, but slightly in BxPC-3. Furthermore, we demonstrated that miR-146b-3p directly targeted MAP3K10 and might activate Hedgehog pathway as well through DYRK2 and GLI2. Conclusions: These results suggest that P-CSCs have distinct gene expression profiles. MiR-146b-3p inhibits proliferation and induced apoptosis in P-CSCs high cells lines by targeting MAP3K10. Targeting P-CSCs specific genes may provide novel strategies for therapeutic purposes.

The patterns of antisense long non-coding RNAs regulating corresponding sense genes in human cancers.

For decades researches of genomic transcription of all kinds of species have demonstrated that the important role of Long non-coding RNAs (LncRNAs) in whole process of life entity has been more and more attached. Owing to constant developing of advanced technology, especially the emerge of next generation sequencing, researchers could explore further in the depth and breadth of LncRNAs. Given that the unique RNA loci location with its corresponding sense gene, antisense long noncoding RNAs (AS-lncRNAs), which are one of the main categories of LncRNAs classification, would have existed an identified close connection between them in a natural physiological state. This review characterizes the patterns of regulation between AS-lncRNAs and corresponding sense genes during the process of cancer progression in human, with emphases on the regular modulation ways of the potential molecular mechanism of AS-lncRNAs and the summary of underlying treatment targets in human cancers.

Predictive factors of postoperative pancreatic fistula after laparoscopic pancreatoduodenectomy.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) continues to be a major contributor to morbidity after pancreaticoduodenectomy (PD), but it remains unclear what risk factors can precisely predict the development of CR-POPF after laparoscopic pancreatoduodenectomy (LPD). We thus aimed to identify the risk factors for predicting CR-POPF after LPD. METHODS: A total of 388 consecutive patients who underwent LPD at our institution between July 2014 and December 2018 were identified. All data, including pre-, intra-, and postoperative risk factors associated with CR-POPF defined by the International Study Group of Pancreatic Fistula, were collected retrospectively. To evaluate the predictive performance of the risk factor models, areas under the receiver operating characteristic curve (ROC) were determined. RESULTS: CR-POPF was observed in 31 patients (8.0%) with significant association observed with body mass index (BMI), visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA), intra-abdominal fat thickness, main pancreatic duct width, soft pancreatic texture, operative time, underlying pathology, and albumin (Alb) on postoperative days (POD) 1--3. Multivariate analyses revealed that VFA >82 cm2 [odds ratio (OR) =11.088; P=0.029], main pancreatic duct width <3 mm (OR =7.701; P=0.001), soft pancreatic texture (OR =12.543; P=0.022), and operative time >320 min (OR =6.061; P<0.001) were independent risk factors for CR-POPF after LPD. Areas under the ROC curve (AUC) analysis revealed the pancreatic texture was the strongest single predictor (AUC =0.854) of CR-POPF, and pancreatic texture + pancreatic duct width was the best two-predictor model (AUC =0.904). Meanwhile, our findings indicated an association between the TFA >221 cm2 (OR =8.637; P=0.001) and VFA >82 cm2 (OR =7.009; P<0.001) with soft pancreatic texture. CONCLUSIONS: Soft pancreatic texture, VFA >82 cm2, main pancreatic duct width <3 mm, and operative time >320 min were independent predictive risk factors of CR-POPF for LPD.

Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal human cancers. N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive. METHODS: LC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14. RESULTS: We found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells. CONCLUSIONS: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

Diagnostic Value of Plasma miR-181b, miR-196a, and miR-210 Combination in Pancreatic Cancer.

PURPOSE: This study was aimed at investigating the roles of plasma miR-181b, miR-196a, and miR-210 in the diagnosis of pancreatic cancer (PC). METHODS: Plasma samples were isolated from 40 patients with PC and 40 healthy individuals, respectively. The expression of miR-181b, miR-196a, and miR-210 was detected by qRT-PCR. The level of carbohydrate antigen 199 (CA199) was measured by an electrochemiluminescence (ECL) assay. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of miR-181b, miR-196a, miR-210, CA199, and their combinations in PC. RESULTS: The expression of plasma miR-181b, miR-196a, and miR-210 was significantly upregulated in PC patients. The plasma level of CA199 was also significantly increased in PC patients. The expression of miR-181b, miR-196a, and miR-210 was closely associated with lymph node metastasis, clinical stage, and vascular invasion but not correlated with age, gender, and tumor size. miR-181b, miR-196a, and miR-210 have lower AUC than CA199 in the diagnosis of PC. miR-181b+miR-210 and miR-196a+miR-210 also have lower AUC than CA199. It is worth noting that miR-181b+miR-196a+miR-210 has a higher AUC than CA199 in the diagnosis of PC. CONCLUSION: The combination of plasma miR-181b, miR-196a, and miR-210 had a good diagnostic value for PC.

G Protein-Coupled Receptor GPR87 Promotes the Expansion of PDA Stem Cells through Activating JAK2/STAT3.

Cancer stem cells are the main reason for drug resistance and tumor relapse, and screening the targets for cancer stem cells is essential for tumor therapy. Here, we studied the role and regulatory mechanism of a G protein-coupled receptor named as G protein-coupled receptor 87 (GPR87) in the expansion of pancreatic ductal adenocarcinoma (PDA) stem cells. We found that GPR87 was an independent prognostic factor for PDA patients: patients with high GPR87 had a poor outcome. GPR87 significantly promoted the sphere formation ability, increased side population (SP) cell number, increased the expression of PDA stem cell markers, and increased the tumor initiation ability, suggesting that GPR87 promotes the expansion of PDA stem cells. Mechanism analysis suggested that signal transducer and activator of transcription 3 (STAT3) directly bound to the promoter of GPR87 to increase GPR87 expression; inversely, GPR87 also activated STAT3. Further analysis suggested that GPR87 activated Janus kinase 2 (JAK2), which can activate STAT3, inhibiting JAK2 activation in GPR87-overexpressing PDA cells, which significantly inhibited the expansion of PDA stem cells; these findings suggested that GPR87, JAK2, and STAT3 formed a positive feedback loop increasing PDA stem cell population. In PDA specimens, GPR87 expression is positively correlated with the phosphorylation level of STAT3 and JAK2, confirming GPR87 promoted PDA stem cell expansion through activating JAK2/STAT3. In summary, we found that GPR87, together with JAK2 and STAT3, formed a positive feedback loop to promote the expansion of PDA stem cells.

Long Noncoding RNA RMRP Suppresses the Tumorigenesis of Hepatocellular Carcinoma Through Targeting microRNA-766.

PURPOSE: This study aimed to explore the regulatory effect of long noncoding RNA (lncRNA) ribonuclease mitochondrial RNA processing gene (RMRP) on hepatocellular carcinoma (HCC). METHODS: The expression of RMRP in HCC tissues and cell lines was assessed by qRT-PCR. Kaplan-Meier method was utilized to analyze the correlation between RMRP expression and the survival of HCC patients. MHCC97H and HuH7 cells were transfected with pcDNA3.1-RMRP or pcDNA3.1, respectively. MTT and flow cytometry assays were conducted to examine the proliferation and apoptosis of HCC cells, respectively. The migration and invasion of HCC cells were assessed using wound healing and transwell assays, respectively. StarBase3.0 and dual-luciferase reporter gene assay were used to identify the target relationship between miR-766 and RMRP. A xenografted tumor model was established in rats to evaluate the effect of RMRP in vivo. RESULTS: RMRP was down-regulated in HCC tissues and cells. Low expression of RMRP was correlated with poor survival of HCC patients. The A495 value and colony number were significantly decreased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. The apoptosis rate was significantly increased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. The migration rate and the number of invasive cells were significantly decreased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. MiR-766 was a target of RMRP and eliminated the anti-tumor effect of RMRP on MHCC97H cells. The up-regulation of RMRP suppressed the growth of xenograft tumors in rats. CONCLUSION: Overexpression of RMRP suppressed the tumorigenesis of HCC by targeting miR-766.

Long noncoding RNA LINC01111 suppresses pancreatic cancer aggressiveness by regulating DUSP1 expression via microRNA-3924.

Dysfunction in long noncoding RNAs (lncRNAs) is reported to participate in the initiation and progression of human cancer; however, the biological functions and molecular mechanisms through which lncRNAs affect pancreatic cancer (PC) are largely unknown. Here, we report a novel lncRNA, LINC01111, that is clearly downregulated in PC tissues and plasma of PC patients and acts as a tumor suppressor. We found that the LINC01111 level was negatively correlated with the TNM stage but positively correlated with the survival of PC patients. The overexpression of LINC01111 significantly inhibited cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, the knockdown of LINC01111 enhanced cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Furthermore, we found that high expression levels of LINC01111 upregulated DUSP1 levels by sequestering miR-3924, resulting in the blockage of SAPK phosphorylation and the inactivation of the SAPK/JNK signaling pathway in PC cells and thus inhibiting PC aggressiveness. Overall, these data reveal that LINC01111 is a potential diagnostic biomarker for PC patients, and the newly identified LINC01111/miR-3924/DUSP1 axis can modulate PC initiation and development.