Tumour-associated macrophages and Schwann cells promote perineural invasion via paracrine loop in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by perineural invasion (PNI), which is associated with excruciating neuropathic pain and malignant progression. However, the relationship between PNI and tumour stromal cells has not been clarified. METHODS: The dorsal root ganglia or sciatic nerves nerve model was used to observe the paracrine interaction and the activation effect among Schwann cells, tumour-associated macrophages (TAMs), and pancreatic cancer cells in vitro. Next generation sequencing, enzyme-linked immunosorbent assay and chromatin immunoprecipitation were used to explore the specific paracrine signalling between TAMs and Schwann cells. RESULTS: We demonstrated that more macrophages were expressed around nerves that have been infiltrated by pancreatic cancer cells compared with normal nerves in murine and human PNI specimens. In addition, high expression of CD68 or GFAP is associated with an increased incidence of PNI and indicates a poor 5-year survival rate in patients with PDAC. Mechanistically, tumour-associated macrophages (TAMs) activate Schwann cells via the bFGF/PI3K/Akt/c-myc/GFAP pathway. Schwann cells secrete IL-33 to recruit macrophages into the perineural milieu and facilitate the M2 pro-tumourigenic polarisation of macrophages. CONCLUSIONS: Our study demonstrates that the bFGF/IL-33 positive feedback loop between Schwann cells and TAMs is essential in the process of PNI of PDAC. The bFGF/PI3K/Akt/c-myc/GFAP pathway would open potential avenues for targeted therapy of PDAC.

Effects of RNA methylation on Tumor angiogenesis and cancer progression.

Tumor angiogenesis plays vital roles in the growth and metastasis of cancer. RNA methylation is one of the most common modifications and is widely observed in eukaryotes and prokaryotes. Accumulating studies have revealed that RNA methylation affects the occurrence and development of various tumors. In recent years, RNA methylation has been shown to play an important role in regulating tumor angiogenesis. In this review, we mainly elucidate the mechanisms and functions of RNA methylation on angiogenesis and progression in several cancers. We then shed light on the role of RNA methylation-associated factors and pathways in tumor angiogenesis. Finally, we describe the role of RNA methylation as potential biomarker and novel therapeutic target.

Interaction between intestinal microbiota and tumour immunity in the tumour microenvironment.

In recent years, an increasing number of studies have reported that intestinal microbiota have an important effect on tumour immunity by affecting the tumour microenvironment (TME). The intestinal microbiota are closely associated with various immune cells, such as T lymphocytes, natural killer cells (NK cells) and macrophages. Some bacteria, such as Akkermansia muciniphila (A. muciniphila) and Lactobacillus reuteri (L. reuteri), have been shown to improve the effect of tumour immunity. Furthermore, microbial imbalance, such as the increased abundance of Fusobacterium nucleatum (F. nucleatum) and Helicobacter hepaticus (H. hepaticus), generally causes tumour formation and progression. In addition, some microbiota also play important roles in tumour immunotherapy, especially PD-L1-related therapies. Therefore, what is the relationship between these processes and how do they affect each other? In this review, we summarize the interactions and corresponding mechanisms among the intestinal microbiota, immune system and TME to facilitate the research and development of new targeted drugs and provide new approaches to tumour therapy.

A novel anastomosis technique facilitates pancreaticojejunostomy in total laparoscopic pancreaticoduodenectomy (with video).

BACKGROUND: While the best technique for pancreatic anastomosis during Whipple's procedure remains controversial, laparoscopic pancreaticoduodenectomy (LPD) has been rapidly increasing in popularity. Because of their feasibility and reliability, new pancreatic anastomosis techniques may have vital roles when adapted for LPD. Here, we describe a new pancreaticojejunostomy (PJ) technique using three sutures (termed the "three sutures" PJ technique), which facilitates pancreatic anastomosis during total LPD. METHODS: A total of 149 patients who underwent LPD using the "three sutures" PJ technique at three hospitals were included in this study (81 patients at Guangdong Provincial People's Hospital [GDPH], 60 patients at Sun Yat-Sen Memorial Hospital [SMH], and 8 patients at Affiliated Hospital of Guangdong Medical University [AHGMU]). Data on the demographic characteristics, operative outcomes, and postoperative results (pancreatic fistula rate, mortality rate, and length of hospital stay) of these patients were collected and analyzed. RESULTS: A surgical video showing the details of the "three sutures" PJ method was included. The mean operation times at GDPH, SMH, and AHGMU were 4.08 ± 0.99 h, 4.65 ± 1.53 h, and 4.67 ± 0.64 h, respectively, and the average PJ times were 17.96 ± 3.49 min, 18.19 ± 2.63 min, and 22.5 ± 3.96 min, respectively. The numbers of grade B pancreatic fistulas were 9 (11.11%), 2 (3.33%), and 1 (12.50%), respectively, and two patients had grade C fistulas, one each at GDPH and SMH. The numbers of clinically relevant postoperative pancreatic fistula (CR-POPF) were 10 (12.35%), 3 (5.00%), and 1 (12.50%) in each center, respectively. The overall rate of CR-POPF was 9.40% (14/149) among patients of all three centers. The perioperative mortality rate was 0%. CONCLUSIONS: The "three sutures" PJ technique for total LPD is a safe and reliable method, with a low risk of pancreatic fistula, short anastomosis time, and steep learning curve.

Roles of circRNAs in the tumour microenvironment.

The tumour microenvironment (TME) constitutes the area surrounding the tumour during its development and has been demonstrated to play roles in cancer-related diseases through crosstalk with tumour cells. Circular RNAs (circRNAs) are a subpopulation of endogenous noncoding RNAs (ncRNAs) that are ubiquitously expressed in eukaryotes and have multiple biological functions in the regulation of cancer onset and progression. An increasing number of studies have shown that circRNAs participate in the multifaceted biological regulation of the TME. However, details on the mechanisms involved have remained elusive until now. In this review, we analyse the effects of circRNAs on the TME from various perspectives, including immune surveillance, angiogenesis, hypoxia, matrix remodelling, exo-circRNAs and chemoradiation resistance. Currently, the enormous potential for circRNA use in targeted therapy and as noninvasive biomarkers have drawn our attention. We emphasize the prospect of targeting circRNAs as an essential strategy to regulate TME, overcome cancer resistance and improve therapeutic outcomes.

Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis.

BACKGROUND: Accumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear. METHOD: CircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p. RESULTS: In the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo. CONCLUSIONS: Our findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.

Exosomal circRNAs: biogenesis, effect and application in human diseases.

Exosomes have emerged as critical mediators of intercellular communication, both locally and systemically, by regulating a diverse range of biological processes between cells. Circular RNA (circRNA) is a novel member of endogenous noncoding RNAs with widespread distribution and diverse cellular functions. Recently, circular RNAs have been identified for their enrichment and stability in exosomes. In this review, we outline the origin, biogenesis and function of exosomal circRNAs as well as their roles in various diseases. Although their precise roles and mechanisms of gene regulation remain largely elusive, exosomal circRNAs have potential applications as disease biomarkers and novel therapeutic targets.

Effects of exosomes on pre-metastatic niche formation in tumors.

A pre-metastatic niche is a microenvironment prepared for the colonization of circulating tumor cells in specific organs. Exosomes are extracellular vesicles with a variety of biological functions. Exosomes play an irreplaceable role in the development of pre-metastatic niches, and mainly function as communication medium. In this review, we analyzed the effects of exosomes on pre-metastatic niches from various perspectives, including inflammation, immune response, angiogenesis, organotropism, matrix remodeling and biomarker expression. In particular, exosomes express programmed death ligand 1 (PD-L1) and cause the immune escape of tumor cells. The immunomodulatory effects of exosomes and their potential in liquid diagnosis have drawn our attention. The potential value of exosomes and pre-metastatic niches will be realized in the field of immunity therapy.

Effect of exosomal miRNA on cancer biology and clinical applications.

Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics.

Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment.

Exosomes are extracellular vesicles released by many cell types and have been attributed for their roles in many diseases including cancer. Exosomes secreted by tumor cells and stromal cells are critical mediators of intercellular communication in tumor microenvironments. Long noncoding RNAs (lncRNAs) are selectively sorted into exosomes and can regulate cancer onset and progression in a variety of ways. In this review, we summarize the characteristics of exosomal lncRNAs and their dysregulation in multiple types of cancer. We provide an overview of current research on exosomal lncRNAs in tumor microenvironments, especially the functions of exosomal lncRNAs in regulating tumor biology. A deeper understanding of the role of exosomal lncRNAs in the tumor microenvironment may help provide new diagnostic and prognostic markers for cancer.

The Biological Effect and Clinical Application of Long Noncoding RNAs in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignancies in the world. Easier recurrence and metastasis is the main cause of mortality in CRC patients, and the markers applied for diagnosis and treatment of CRC is still urgently needed to early diagnose and evaluate therapeutic effect. Long noncoding RNA (lncRNA) is a class of noncoding RNA that the length is more than 200 nucleotides. With the development of sequencing technique about transcriptome, increasing lncRNAs are focused on their function and mechanism related to the nosogenesis and pathology of CRC. Recent studies report that lncRNAs acted as crucial role in CRC and could be as biomarker for CRC diagnosis and treatment. In this review, we display the regulation of lncRNA by interacting with DNA, RNA and protein and highlight the double role of lncRNAs as oncogene or anti-tumor gene involved in Wnt signaling pathway, p53 signaling pathway or others to be an regulator in CRC development. Lastly, we discuss some new finding of lncRNAs, especially lncRNA in exosome, which could be as potential markers for diagnosis and treatment of CRC in future.

Detection of EGFR expression in patients with colorectal cancer and the therapeutic effect of cetuximab.

PURPOSE: This study was designed to detect the expression of epidermal growth factor receptor (EGFR) in tumor specimens of patients with colorectal cancer (CRC); moreover, the relationship between EGFR expression and clinical factors as well as prognosis were analyzed to provide a basis for individualized treatment of CRC. METHODS: This study used paraffin-embedded tumor specimens of 70 CRC patients who were treated with cetuximab. Immunohistochemistry (IHC) was used to detect the expression of EGFR in CRC tumor specimens. The patient clinical features and treatment administered were recorded and then, the therapeutic effect of cetuximab was evaluated. Progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: The positive expression rate of EGFR was 64% (45/70), while 18 patients had negative expression. Twenty-two cases had weak positive expression, 15 cases positive expression and another 15 strongly positive expression. Of 70 specimens, 27 (38.6%) had high EGFR expression belonging to 20 (50%) males and 7 (23%) females (p<0.05). However, age, Karnofsky performance status (KPS), tumor site, grade of differentiation and clinical stage showed no significant difference in relation to EGFR expression (p>0.05). No patient achieved complete remission (CR), 15 (21.4%) had partial remission (PR), 12 (17.1%) were in stable state (SD) and 40 (57.1%) patients had disease progression (PD). Disease control rate (DCR) was 39.02% (16/41) in the group with low EGFR expression and 48.28% (14/29) in the group with high EGFR expression (p>0.05). CONCLUSION: EGFR expression in CRC tissue is correlated with patient gender. In the group with higher EGFR expression, the effectiveness of cetuximab was significantly higher than that in the low EGFR expression group, indicating correlation between the high expression of EGFR and the short-term effect of cetuximab.

Radical nerve dissection for the carcinoma of head of pancreas: report of 30 cases.

OBJECTIVE: To explore the clinical value of the radical nerve dissection (RND) for the carcinoma of head of pancreas (CHP). METHODS: The clinical and pathological data of 30 CHP patients who underwent RND in our hospital were retrospectively analyzed, with an attempt to explore the safety and short-term efficacy of this procedure. RESULTS: Among these 30 patients, the operative time was (351±61) min, the intra-operative blood loss was 350 (range, 300-600) mL, and the grades B and C pancreatic fistula was 23.33%. During the follow-up (range, 2-30 months; median: 17 months), the 1-year survival rate was 63.33% and the 1-year disease-free survival rate was 56.67%. Among the 23 patients (76.66%) with positive extra-pancreatic perineural invasion (PNI), the 1-year casefatality rate was 34.78%, which was not significantly different from that (28.57%) of patients with negative PNI (P=0.760). CONCLUSIONS: Our results suggested potential advantages of RND in the fields of surgery-associated risk and prognosis compared with the Whipple operation in the treatment of CHP. Due to the low sample size of this study, further well-designed research of large sample size is needed.

Analysis of global gene expression profiles suggests a role of acute inflammation in type 3C diabetes mellitus caused by pancreatic ductal adenocarcinoma.

AIMS/HYPOTHESIS: Pancreatic ductal adenocarcinoma (PDAC) can cause type 3C diabetes, known as PDAC-associated diabetes mellitus (PDAC-DM), but the mechanism is unknown. This study aimed to reveal the mechanism. METHODS: PDAC lesions from patients with or without PDAC-DM (n = 4 in each group) were individually profiled for 23,512 mRNAs with microarrays. Bioinformatic analysis and in vivo and in vitro assays were then conducted. RESULTS: We determined that 2,778 genes were differentially expressed; over-representation of ten genes was validated with quantitative RT-PCR. The analysis of gene ontology showed that the differentially expressed secretory genes were related mainly to inflammation. High levels of a marker of inflammation (C-reactive protein [CRP]) and an inflammatory mediator (TNF super-family member 13 [TNFSF13]) were found in the serum of patients with PDAC-DM. After surgical resection of PDAC lesions, CRP and TNFSF13 levels significantly decreased (p < 0.01). Furthermore, we found that the levels of TNFSF13 in PDAC lesions and TNFSF13 and CRP in serum were significantly correlated with the diabetic status of patients with PDAC-DM (p < 0.01). Assays in vivo showed that after exposure to an inhibitor of inflammation (celecoxib), the fasting blood glucose level in the mouse model of PDAC-DM dramatically decreased from 6.9 ± 0.1 to 5.6 ± 0.1 mmol/l in 2-4 days (p < 0.01). CONCLUSIONS/INTERPRETATION: We found that acute inflammation was involved in the pathogenesis of PDAC-DM. We contend that acute inflammation is a potential target for the diagnosis and treatment of PDAC-DM.

High expression of AFAP1-AS1 is associated with poor survival and short-term recurrence in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is still a lethal malignancy. Long noncoding RNAs (lncRNAs) have been shown to play a critical role in cancer development and progression. Here we identified overexpression of the lncRNA AFAP1-AS1 in PDAC patients and evaluated its prognostic and functional relevance. METHODS: The global lncRNA expression profile in PDAC was measured by lncRNA microarray. Expression of AFAP1-AS1 was evaluated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) in 90 PDAC tissue samples and adjacent normal tissues. The impact of AFAP1-AS1 expression on cell proliferation, migration, and invasion were evaluated in vitro using knockdown and ectopic expression strategies. RESULTS: Microarray analysis revealed that up-regulation of AFAP1-AS1 expression in PDAC tissues compared with normal adjacent tissues, which was confirmed by RT-qPCR in 69/90 cases (76.7%). Its overexpression was associated with lymph node metastasis, perineural invasion, and poor survival. When using AFAP1-AS1 as a prognostic marker, the areas under ROC curves were 0.8669 and 0.9370 for predicting tumor progression within 6 months and 1 year, respectively. In vitro functional experiments involving knockdown of AFAP1-AS1 resulted in attenuated PDAC cell proliferation, migration, and invasion. Ectopic expression of AFAP1-AS1 promoted cell proliferation, migration, and invasion. CONCLUSIONS: AFAP1-AS1 is a potential novel prognostic marker to predict the clinical outcome of PDAC patients after surgery and may be a rational target for therapy.

The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer.

BACKGROUND: The human genome encodes many long non-coding RNAs (lncRNAs). However, their biological functions, molecular mechanisms, and the prognostic value associated with pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. Here, we identify a fundamental role for the lncRNA HOXA transcript at the distal tip (HOTTIP) in the progression and chemoresistance of PDAC. METHODS: High-throughput microarrays were performed to detect the expression profiles of lncRNAs and messenger RNAs in eight human PDAC tissues and four pancreatic tissues. Quantitative real-time PCR was used to determine the levels of HOTTIP and HOXA13 transcripts in PDAC cell lines and 90 PDAC samples from patients. HPDE6 cells (immortalized human pancreatic ductal epithelial cells) and corresponding adjacent non-neoplastic tissues were used as controls, respectively. The functions of HOTTIP and HOXA13 in cell proliferation, invasion, and epithelial-mesenchymal transition were evaluated by targeted knockdown in vitro. CCK-8 assays, colony formation assays, and xenografts in nude mice were used to investigate whether targeted silencing of HOTTIP could sensitize pancreatic cancer cells to gemcitabine. Immunohistochemistry was performed to investigate the relationship between HOXA13 expression and patient outcome. RESULTS: Microarray analyses revealed that HOTTIP was one of the most significantly upregulated lncRNAs in PDAC tissues compared with pancreatic tissues. Quantitative PCR further verified that HOTTIP levels were increased in PDAC cell lines and patient samples compared with controls. Functionally, HOTTIP silencing resulted in proliferation arrest by altering cell-cycle progression, and impaired cell invasion by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Additionally, inhibition of HOTTIP potentiated the antitumor effects of gemcitabine in vitro and in vivo. Furthermore, knockdown of HOXA13 by RNA interference (siHOXA13) revealed that HOTTIP promoted PDAC cell proliferation, invasion, and chemoresistance, at least partly through regulating HOXA13. Immunohistochemistry results revealed that higher HOXA13 expression was correlated with lymph node metastasis, poor histological differentiation, and decreased overall survival in PDAC patients. CONCLUSIONS: As a crucial tumor promoter, HOTTIP promotes cell proliferation, invasion, and chemoresistance by modulating HOXA13. Therefore, the HOTTIP/HOXA13 axis is a potential therapeutic target and molecular biomarker for PDAC.

Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients.

BACKGROUND: Glutamate dehydrogenase (GDH) is a key enzyme that catalyzes the final reaction of the glutamine metabolic pathway, and has been reported implicated in tumor growth and metastasis. However, it's clinical significance and role in colorectal cancer (CRC) pathogenesis is largely unknown. METHODS: The expression of GDH was determined by qPCR, western blot and immunohistochemistry in CRC cells and samples. The correlation of GDH expression with clinicopathologic features and prognosis was analyzed. The functional role of GDH in CRC cell proliferation, motility and metastasis was evaluated. RESULTS: We found that GDH was up-regulated both in colorectal cancer and metastatic lesions (n = 104). Patients with high GDH expression had poorer overall survival (HR 2.32; 95% CI 1.26-4.26; P = 0.007) and poorer disease-free survival rates (HR 2.48; 95% CI 1.25-4.92; P = 0.009) than those with low GDH expression. Furthermore, we showed that GDH expression was an independent prognostic factor for CRC. In addition, over-expression of GDH promoted cell proliferation, migration and invasion in vitro, whereas loss function of GDH did the opposite. Finally, we demonstrated that the promotion of CRC progression by GDH correlated with activation of STAT3 mediated epithelial-mesenchymal transition (EMT) induction. CONCLUSIONS: These results indicate that GDH plays a critical role in CRC progression, and may provide a novel metabolism therapeutic target for CRC treatment.

Macrophage migration inhibitory factor is overexpressed in pancreatic cancer tissues and impairs insulin secretion function of ß-cell.

BACKGROUND: Understanding the pathogenic mechanism of pancreatic cancer associated diabetes (PCDM) might help yield biomarkers for the early diagnosis of pancreatic cancer (PC) from population with new-onset diabetes. In the current study, we sought to determine the role of macrophage migration inhibitory factor (MIF) in PCDM pathogenesis. METHODS: The protein and mRNA levels of MIF in paraffin-embedded human PC samples, chronic pancreatitis specimens, and normal pancreas were measured by immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction. We measured serum levels of MIF in PC patients and controls. The biologic impacts of MIF overexpression on insulin secretion function of mice islets and ß cells (HIT-T15) were investigated in vitro. RESULTS: MIF expression was significantly increased in pancreatic cancer tissues compared with chronic pancreatitis or normal pancreas specimens. The insulin secretion function of both islets and HIT-T15 cells was impaired by indirect co-cultured with PC cells or treated with conditioned media from them. Stable MIF knock-down significantly decreased the diabetogenic effect of PC cells, while MIF knock-in HPDE6 cells demonstrated a strong inhibitory effect on insulin secretion function of islets and HIT-T15 cells. MIF impaired ßcell function by depressing the Ca⁺ currents, decreasing L-type Ca⁺ channel α1 subunit protein expression level, and enhancing p-Src activity. Mean serum level of MIF was significant higher in new-onset diabetes associated PC patients in comparison with other groups. CONCLUSIONS: MIF is up-regulated in patients with pancreatic cancer and causes dysfunction of insulin secretion in ß-cells.

Flagellin modulates TIM4 expression in mast cells.

T-helper (Th) 2 polarization functions in a number of immune diseases, but their pathogenesis needs further investigation. Some microbial products or components are strong adjuvants in the creation of mouse models of Th2 polarization. T cell immunoglobulin mucin molecule (TIM) 4 is a facilitator in the initiation of Th2 response. This study looks at the role of one of the microbial products, flagellin (FGN), in the induction of TIM4 expression in mast cells. Bone marrow derived mast cells (BMMC) were generated. Induction of TIM4 in mast cells was assessed in both experiments in vitro and in vivo. The signal transducer and activator of transcription 6 (Stat6) phosphorylation in BMMC were assessed by Western blotting. A coculture model with FGN-primed BMMC and naïve CD4(+) T cells was employed to assess FGN in facilitating the expression of TIM4 in mast cells. After exposure to FGN, TIM4 levels were significantly increased in BMMC and mast cells of the mouse intestine, which was accompanied by increased STAT6 phosphorylation. Culture with FGN-primed BMMC, naïve CD4(+) T cells developed into Th2 cells by a TIM4-dependent manner. We conclude that FGN can induce mast cells to express TIM4, which helps initiate Th2 polarization.

Nudt21-mediated alternative polyadenylation of MZT1 3'UTR contributes to pancreatic cancer progression.

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and is involved in many diseases, but its function and mechanism in regulating pancreatic cancer (PC) pathogenesis remain unclear. In this study, we found that the 3' UTR shortening of MZT1 was the most prominent APA event in PC liver metastases. The short-3'UTR isoform exerted a stronger effect in promoting cell proliferation and migration both in vitro and in vivo. NUDT21, a core cleavage factor involved in APA, promoted the usage of proximal polyadenylation sites (PASs) on MZT1 mRNA by binding to the UGUA element located upstream of the proximal PAS. High percentage of distal polyA site usage index of MZT1 was significantly associated with a better prognosis. These findings demonstrate a crucial mechanism that NUDT21-mediated APA of MZT1 could promote the progression of PC. Our findings provided a better understanding of the connection between PC progression and APA machinery.