Pancreatic Cancer Tumorigenesis Research Articles

6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling

BackgroundThe underlying mechanism behind the tumorigenesis and progression of pancreatic cancer is not clear, and treatment failure is generally caused by early metastasis, recurrence, drug resistance and vascular invasion. Exploring novel therapeutic regimens is necessary to overcome drug resistance and improve patients outcomes.MethodsFunctional assays were performed to investigate the role of [6]-Paradol (6-P) in proliferation and metastasis of pancreatic cancer in vitro and in vivo. The interaction between EGFR and 6-P was tested by KEGG enrichment analysis and molecular docking analysis. qRT-PCR was performed to detect the mRNA expression of EGFR in 6-P treated groups. Involvement of the PI3K/AKT pathway was measured by western blotting.Results6-P significantly suppressed pancreatic cancer cell proliferation and metastasis. KEGG enrichment analysis and molecular docking analysis suggested that there existed certain interaction between EGFR and 6-P. In addition, 6-P obviously decreased EGFR protein expression level but did not change the mRNA expression level of EGFR. 6-P could induce degradation of EGFR through decreasing the protein stability of EGFR and enhancing the ubiquitin-mediated proteasome-dependent degradation, 6-P-mediated EGFR degradation led to inactivation of PI3K/AKT signaling pathway. However, ectopic expression of EGFR protein resulted in resistance to 6-P-mediated inactivity of PI3K/AKT signaling and inhibition of malignant phenotype of pancreatic cancer. Inversely, erlotinib could enhance the 6-P-mediated anticancer activity.ConclusionOur data indicated that 6-P/EGFR/PI3K/AKT signaling axis might become one of the potential therapies for the treatment of pancreatic cancer.

MiRNA‑7515 suppresses pancreatic cancer cell proliferation, migration and invasion via downregulating IGF‑1 expression.

Pancreatic cancer (PC) is a lethal malignancy of the gastrointestinal tract. Previous studies have reported that microRNAs (miRNAs/miRs) are involved in the tumorigenesis of PC. Therefore, the present study aimed to determine the effects of miR-7515 on PC cell proliferation, invasion and migration in vitro and in vivo, and investigate its underlying molecular mechanism using bioinformatics, double luciferase assay and western blotting. The results revealed that the expression levels of miR-7515 were downregulated in PC, which predicted a poor clinical outcome. The overexpression of miR-7515 significantly decreased the proliferation, invasive and migratory abilities of PC cells in vitro and in vivo, while the knockdown of miR-7515 exerted the opposite effects. miR-7515 was identified to directly bind to insulin-like growth factor 1 (IGF-1) and downregulate its expression, which subsequently downregulated the Ras/Raf/MEK/ERK signalling pathway. The overexpression of IGF-1 reversed the inhibitory effects of miR-7515 overexpression on PC cells. In conclusion, the findings of the present study indicated that miR-7515 may act as a tumor suppressor in PC, as it repressed PC cell proliferation invasion and migration via downregulating the expression of IGF-1 and the activity of the Ras/Raf/MEK/ERK signalling pathways.

Abstract 116: Stromal expression of the synaptic protein netrin G1 ligand (NGL-1) promotes tumorigenesis and immunosuppression in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly types of cancer, with a 5-year survival of only 10%. One of the major features of PDAC is the dense fibrous stroma, due to the expansion of cancer associated fibroblasts (CAFs) and their extracellular matrix (ECM). This unique environment promotes immunosuppression, lack of nutrients and exclusion or inactivation of antitumor immune cells, representing a challenge for therapies. Recently, we identified the ectopic expression of the neuronal protein Netrin G1 Ligand (NGL-1) in PDAC tissue, including its novel expression in immune cells and CAFs. However, the roles of NGL-1 in the microenvironment of PDAC and in immune cell function are unknown and deserved further investigation. The effects in tumorigenesis were evaluated by orthotopically injecting pancreatic tumor cells in wild-type and NGL-1 full body knockout mice. The roles of NGL-1 in the pro-tumor functions of CAFs were evaluated using our in vitro 3D system, and questioning if NGL-1+ CAFs, compared to NGL-1 knockdown CAFs (CRISPRi), are able to rescue PDAC cell survival under nutrient deprivation, and discern their immunosuppressive profile. For the translational approach, we assessed the overall survival of 140 PDAC patients according to NGL-1 expression in the TME. Myeloid, T and NK cells from tumor-bearing mice tended to overexpress NGL-1 when compared with cells from naïve mice. Moreover, CD8+ and CD4+ T cells from NGL-1 KO mice proliferated more when stimulated in vitro, suggesting that NGL-1 could represent a functional brake for T cells. Moreover, the lack of NGL-1 in stimulated bone marrow-derived macrophages decreased pro-inflammatory cytokine secretion, further suggesting a functional role for NGL-1 in myeloid cells. Of note, NGL-1 KO mice orthotopically injected with PDAC cells developed smaller tumors with decreased secretion of immunosuppressive factors. In accordance, NGL-1 knockdown CAFs did not support PDAC cell survival in vitro and produced less immunosuppressive cytokines, which was phenocopied by the treatment with a peptide targeting NGL-1. Finally, the low expression of NGL-1 in CAFs and immune cells correlated with better survival of PDAC patients, therefore underscoring NGL-1 as a potential new target in PDAC, that could be manipulated in different compartments in pancreatic cancer (cancer cells, CAFs, immune cells). Citation Format: Debora B. Vendramini-Costa, Ralph Francescone, Tiffany Luong, Janusz Franco-Barraza, Igor Astsaturov, Kathy Q. Cai, Andres J. Klein-Szanto, Huamin Wang, Kerry S. Campbell, Edna Cukierman. Stromal expression of the synaptic protein netrin G1 ligand (NGL-1) promotes tumorigenesis and immunosuppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 116.

LncRNA CERS6-AS1 promotes proliferation and metastasis through the upregulation of YWHAG and activation of ERK signaling in pancreatic cancer

LncRNAs play essential regulatory roles in pancreatic cancer (PC) tumorigenesis and progression. We aimed to investigate the role of lncRNA CERS6-AS1 in PC. CERS6-AS1 expression was determined in PC tissues and cell lines by PCR analysis. The roles of CERS6-AS1 on proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) were confirmed via CCK-8 assay, EDU assay, transwell assay, wound healing assay, and western blot assay. Besides, the interaction between CERS6-AS1 and their target genes was verified by luciferase report assays and RIP assays. Animal assays and clinical data analysis were performed to validate the functions in vivo. We found that lncRNA CERS6-AS1 was highly expressed in PC tissues and cells. Additionally, high expression of CERS6-AS1 was obviously associated with poor prognosis. Functional assays demonstrated that CERS6-AS1 downregulation significantly inhibited PC cell growth and migration. Moreover, CERS6-AS1 exerted as a molecular sponge for miR-217-5p (miR-217), and miR-217 was confirmed as a potential target of CERS6-AS1. Subsequently, miR-217 suppressed PC cell proliferation and metastasis by directly targeting YWHAG, which interacted with RAF1 and promoted its phosphorylation, leading to RAF1-mediated ERK signaling activation and translocation of phosphorylated ERK from the cytoplasm to the nucleus. Mechanically, CERS6-AS1 silencing significantly inhibited PC cell proliferation and metastasis via a miR-217/YWHAG/RAF1 signaling axis. CERS6-AS1 exerts as a carcinogen in PC to promote malignant features and behaves as a competitive endogenous RNA for miR-217. We identified CERS6-AS1 as a potential biomarker or therapeutic target to improve PC diagnosis and treatment outcomes.

RETRACTED: m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylating PJA2 and inhibiting Wnt signaling

Pancreatic cancer is the deadliest malignancy of the digestive system and is the seventh most common cause of cancer-related deaths worldwide. The incidence and mortality of pancreatic cancer continue to increase, and its 5-year survival rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most abundant reversible RNA modification in various eukaryotic messenger and long noncoding RNAs and plays crucial roles in the occurrence and development of cancers. However, the role of m6A in pancreatic cancer remains unclear. The present study aimed to explore the role of m6A and its regulators in pancreatic cancer and assess its underlying molecular mechanism associated with pancreatic cancer cell proliferation, invasion, and metastasis. Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. Altogether, this study describes new, potential molecular therapeutic targets for pancreatic cancer that could pave the way to improve patient outcome.

SIRT1 coordinates with the CRL4B complex to regulate pancreatic cancer stem cells to promote tumorigenesis

Pancreatic cancer is a common malignant tumor with poor prognosis. Recently, cancer stem cells (CSCs) were identified in several solid tumors, including pancreatic cancer. Although accumulating evidence indicates that sirtuin 1 (SIRT1) exerts biological functions in various cancers, how it contributes to tumorigenesis and metastasis of pancreatic cancer, as well as its role in CSCs, is still poorly defined. Here we show that SIRT1 interacts with the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex, which is responsible for H2AK119 monoubiquitination (H2AK119ub1), collaborating as a functional unit. Genome-wide analysis of SIRT1/CUL4B targets identified a cohort of genes, including GRHL3 and FOXO3, critically involved in cell differentiation, growth, and migration. Furthermore, we found that SIRT1 and CUL4B collectively promote the proliferation, autophagy, and invasion of pancreatic cancer cells. Remarkably, we demonstrate that SIRT1/CUL4B promotes CSC-like properties, including increased stemness marker expression and sphere formation. In vivo experiments implied that SIRT1 promoted established tumor xenograft growth, increased tumor-initiating capacity in NOD/SCID mice, and increased CSC frequency. Strikingly, SIRT1 and CUL4B expression is markedly upregulated in a variety of human cancers, including pancreatic cancer. Our data provide a molecular basis for the functional interplay between histone deacetylation and ubiquitination. The results also implicate the SIRT1/CRL4B complex in pancreatic cancer metastasis and stem cell properties, thus supporting SIRT1 as a promising potential target for cancer therapy development.

Silencing of Carboxypeptidase E expression inhibits proliferation and invasion of Panc-1 pancreatic cancer cells

Background: Pancreatic cancer is one of the leading cause of cancer-related death globally. The molecular basis of this disease is complex and not fully understood. Previous studies have indicated that carboxypeptidase E (CPE) plays a role in promoting tumorigenesis in many cancer types. Here we have investigated the effect of carboxypeptidase E (CPE), including its isoform, in regulating the proliferation, migration and invasion of Panc-1 cells, a pancreatic cell line. Methods: Panc-1 cells were transfected with CPE siRNA which targets both CPE-wild type and its isoform, or scrambled siRNA, for 24 h and then assayed for proliferation by the MTT and colony formation assays, and migration and invasion by wound healing and matrigel assays, respectively. Results: CPE siRNA treatment of Panc-1 cells down-regulated the expression of CPE mRNA by 94.8%. Silencing of CPE mRNA expression resulted in a significant decrease in proliferation as revealed by the MTT assay and a 62.8% decrease in colony formation. Western blot analysis of expression of Cyclin D1 in Panc-1 cells treated with CPE siRNA showed a decrease of 32.5% compared to scr siRNA treated cells, indicating that CPE regulates proliferation through modulating this cell cycle protein. Additionally, suppression of CPE expression in Panc-1 cells significantly decreased migration and invasion. Conclusions: Our findings indicate that CPE may play an important role in regulating cell proliferation, migration and invasion to promote pancreatic cancer tumorigenesis.

Reduced kinase D‑interacting substrate of 220kDa (Kidins220) in pancreatic cancer promotes EGFR/ERK signalling and disease progression.

Kidins220 is a transmembrane scaffold protein involved in several types of cancer. The aim of the present study was to examine the role of Kidins220 in tumorigenesis and disease progression of pancreatic cancer. The relevant signalling pathways including EGFR, EMT, and MMP were also investigated. The expression of Kidins220 was examined at the transcript and protein level. The Kidins220 knockdown cell model was established and its influence on cellular functions was determined. Involvement of Kidins220 in tumorigenesis and metastasis was examined in CD1 mice, respectively. The results showed that, reduced Kidin220 expression was associated with tumorigenesis, metastasis, and overall survival of pancreatic cancer. Knockdown of Kidins220 promoted proliferation, colony formation and tumorigenic capacity of pancreatic cancer cells invitro and invivo, respectively. Kidins220 regulated pancreatic cancer cell migration through the EGFR/AKT/ERK signalling pathway. Furthermore, enhanced EMT was observed in the pancreatic cancer cell lines with the knockdown of Kidins220, underlying EGFR regulation. Kidins220 also affected cell invasion via MMP1. A reduced expression of Kidins220 was observed in pancreatic cancer, which is associated with disease progression, distant metastasis and poor prognosis. The loss of Kidins220 in pancreatic cancer may contribute to disease progression through the upregulation of EGFR and downstream signalling.

Circ_03955 promotes pancreatic cancer tumorigenesis and Warburg effect by targeting the miR-3662/HIF-1α axis.

Former studies found that circRNAs play an important part in the occurrence of a variety of malignant biological characteristics that are critical for cancer progression. It has been shown that circ_03955 is highly expressed and implicated with quantities of biological processes in solid tumor. However, whether circ_03955 regulates the tumorigenesis and Warburg effect of pancreatic cancer (PC) remains largely unknown. The level of circ_03955 in PC tissues and cell lines was determined by real-time qPCR (RT-qPCR). Loss-of-function and gain-of-function assays were employed to investigate the biological role of circ_03955 in cell proliferation, apoptosis, and glycolysis. RT-qPCR, western blotting, bioinformatics analysis, luciferase reporter assay, and in vivo tumorigenicity assay were employed to determine the underlying mechanisms. In this study, it was investigated that circ_03955 was up-regulated in PC clinical samples as well as PC cell lines and associated with poor clinical outcomes of PC patients. Functional assays revealed that circ_03955 exerts a certain stimulative effect on the growth of PC cells in vitro and in vivo. Circ_03955 also inhibited apoptosis and promotes Warburg effect in PC cells. Mechanistically, bioinformatics analysis indicated that circ_03955 acts as a sponge for microRNA (miR)-3662, and hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional targets of miR-3662. Importantly, genetic promoting of HIF-1ɑ or downregulation of miR-3662 largely compromised circ_03955 depletion mediated tumor-inhibiting effects. Taken together, circ_03955 functions as a tumor promoter through miR-3662/HIF-1α axis, which might provide a novel sight for PC treatment.

LncRNA GATA3‑AS1‑miR‑30b‑5p‑Tex10 axis modulates tumorigenesis in pancreatic cancer

Long noncoding RNAs (lncRNAs) have been widely recognized to play an important role in a variety of diseases. Abnormal regulation of lncRNA GATA3-antisense RNA 1 (AS1) occurs in several cancers, but whether it is involved in the progression of pancreatic cancer (PC) remains unknown. The present study aimed to investigate the biological effects of GATA3-AS1 in PC and to explore the underlying molecular mechanisms. Upregulation of GATA3-AS1 was revealed in PC tissues and cell lines. Knockdown of GATA3-AS1 in PANC-1 or AsPC-1 cells markedly reduced cell viability, cell proliferation, and cell invasion abilities, while cell apoptosis was increased. In addition, GATA3-AS1 knockdown suppressed the stemness of PANC-1 and AsPC-1 cells by decreasing the spheroid formation ability. A tumor xenograft in vivo assay demonstrated that GATA3-AS1 knockdown inhibited tumorigenicity of AsPC-1 cells. Furthermore, the microRNA (miR)-30b-5p downregulation and GATA3-AS1 upregulation were revealed in PC tissues and cell lines. Negative correlations were present between GATA3-AS1 and miR-30b-5p and between miR-30b-5p and testis-expressed protein 10 (Tex10) in the PC tissues, while GATA3-AS1 and Tex10 were positively correlated. GATA3-AS1 was then revealed to act as a competing endogenous RNA (ceRNA) for miR-30b-5p in regulating Tex10 expression. Moreover, the miR-30b-5p-Tex10 axis was confirmed to be involved in the regulation of biological effects of GATA3-AS1, including cell viability, cell proliferation, cell invasion, cell apoptosis, and cell stemness, as well as Wnt1/β-catenin signaling. Collectively, these data indicated that the GATA3-AS1-miR-30b-5p-Tex10 axis modulates tumorigenesis in PC, which may be associated with the Wnt/β-catenin signaling pathway.

LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis.

Pancreatic cancer (PC) is one of the most lethal human malignancies without effective treatment. In an effort to discover key genes and molecular pathways underlying PC growth, we have identified LIM domain only 7 (LMO7) as an under-investigated molecule, which highly expresses in primary and metastatic human and mouse PC with the potential of impacting PC tumorigenesis and metastasis. Using genetic methods with siRNA, shRNA, and CRISPR-Cas9, we have successfully generated stable mouse PC cells with LMO7 knockdown or knockout. Using these cells with loss of LMO7 function, we have demonstrated that intrinsic LMO7 defect significantly suppresses PC cell proliferation, anchorage-free colony formation, and mobility in vitro and slows orthotopic PC tumor growth and metastasis in vivo. Mechanistic studies demonstrated that loss of LMO7 function causes PC cell-cycle arrest and apoptosis. These data indicate that LMO7 functions as an independent and unrecognized druggable factor significantly impacting PC growth and metastasis, which could be harnessed for developing a new targeted therapy for PC.

M6A-Mediated Upregulation of LINC00857 Promotes Pancreatic Cancer Tumorigenesis by Regulating the miR-150-5p/E2F3 Axis.

The mortality and morbidity rates of pancreatic cancer (PC) have been increasing over the past two decades. Recent evidence indicates that long non-coding RNAs (lncRNAs) are usually dysregulated in the tumorigenesis and progression of PC. In the present study, we showed that the expression of LINC00857 was upregulated in PC and associated with poor prognosis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database and validated in our PC tissues and cell lines. N6-Methyladenosine (m6A) was highly enriched within LINC00857 and enhanced its RNA stability. Knockdown of LINC00857 remarkably inhibited the proliferation and promoted the apoptosis of PC cells. Then, by using bioinformation analysis and verified experiments, we identified that LINC00857 functioned as a competing endogenous RNA (ceRNA) for sponging miR-150-5p, leading to the upregulation of its target E2F3 in PC cells. Taken above, our study revealed a potential ceRNA regulatory pathway in which LINC00857 modulates E2F3 expression by binding to miR-150-5p, ultimately promoting tumorigenesis in PC. LINC00857/miR-150-5p/E2F3 regulatory axis may be taken as an alternative therapeutic target for treating PC.

ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis.MethodsThe expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR).ResultsIn this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.ConclusionHence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.

Up-regulation of S100P predicts the poor long-term survival and construction of prognostic signature for survival and immunotherapy in patients with pancreatic cancer

ABSTRACT Pancreatic cancer is associated with a high mortality rate, and the prognosis is positively related to immune status. In this study, we constructed a prognostic signature from survival- and immune-related genes (IRGs) to guide treatment and assess prognosis of patients with pancreatic cancer. The transcriptomic data were obtained from The Cancer Genome Atlas (TCGA) database, and IRGs were extracted from the ImmPort database. Univariate and LASSO regression analysis were used to obtain survival-related IRGs. Finally, the prognostic signature was constructed using multivariate regression analysis. The laboratory experiments were conducted to verify the key IRG expression. Immune cells infiltration was analyzed using the CIBERSORT algorithm and TIMER database. Prognostic signature containing four IRGs (ADA2, TLR1, PTPN6, S100P) was constructed with good predictive performance; in particular, S100P played a significant role in the immune microenvironment, and tumorigenesis of pancreatic cancer. Moreover, we found that CD8+ T cell and activated CD4+ memory T cell tumor infiltration was lower in the high-risk group, while high-risk score correlated positively with higher tumor mutational burden, and the higher half inhibitory centration 50 of chemotherapeutic agents Docetaxel and Sunitinib. In summary, this study identified and constructed an immune-related prognostic signature that can predict overall survival, besides suggests that S100P was a novel immune-related biomarker. We hope that this signature will aid the identification of new biomarkers for the individualized immunotherapy of pancreatic cancer.

Long noncoding RNA LINC00941 promotes pancreatic cancer progression by competitively binding miR-335-5p to regulate ROCK1-mediated LIMK1/Cofilin-1 signaling

An accumulation of evidence indicates that long noncoding RNAs are involved in the tumorigenesis and progression of pancreatic cancer (PC). In this study, we investigated the functions and molecular mechanism of action of LINC00941 in PC. Quantitative PCR was used to examine the expression of LINC00941 and miR-335-5p in PC tissues and cell lines, and to investigate the correlation between LINC00941 expression and clinicopathological features. Plasmid vectors or lentiviruses were used to manipulate the expression of LINC00941, miR-335-5p, and ROCK1 in PC cell lines. Gain or loss-of-function assays and mechanistic assays were employed to verify the roles of LINC00941, miR-335-5p, and ROCK1 in PC cell growth and metastasis, both in vivo and in vitro. LINC00941 and ROCK1 were found to be highly expressed in PC, while miR-335-5p exhibited low expression. High LINC00941 expression was strongly associated with larger tumor size, lymph node metastasis, and poor prognosis. Functional experiments revealed that LINC00941 silencing significantly suppressed PC cell growth, metastasis and epithelial–mesenchymal transition. LINC00941 functioned as a molecular sponge for miR-335-5p, and a competitive endogenous RNA (ceRNA) for ROCK1, promoting ROCK1 upregulation, and LIMK1/Cofilin-1 pathway activation. Our observations lead us to conclude that LINC00941 functions as an oncogene in PC progression, behaving as a ceRNA for miR-335-5p binding. LINC00941 may therefore have potential utility as a diagnostic and treatment target in this disease.

Circular RNA in pancreatic cancer: a novel avenue for the roles of diagnosis and treatment.

Pancreatic cancer (PC), an important cause of cancer-related deaths worldwide, is one of the most malignant cancers characterized by a dismal prognosis. Circular RNAs (circRNAs), a class of endogenous ncRNAs with unique covalently closed loops, have attracted great attention in regard to various diseases, especially cancers. Compelling studies have suggested that circRNAs are aberrantly expressed in different cancer tissues and cell types, including PC. More specifically, circRNAs can modify the proliferation, progression, tumorigenesis and chemosensitivity of PC, and some circRNAs could serve as biomarkers for diagnosis and prognosis. Herein, we summarize what is currently known to be related to the biogenesis, functions and potential roles of human circRNAs in PC and their application prospects for PC clinical treatments.

MUC4 is a novel mediator in H. pylori infection-related pancreatic cancer.

Pancreatic cancer (PC) is a common malignant disease worldwide. Among the potential pathogenic factors, Helicobacter pylori (H. pylori) infection has been associated with the tumorigenesis of PC. The present study aimed to identify the differentially expressed genes (DEGs) of H. pylori infection-associated PC and to investigate the key factors involved in PC tumorigenesis. Using bioinformatics methods, overlapping DEGs and key gene were identified from H. pylori-infected gastric mucosa (GM) and H. pylori infection-associated PC. Survival and tumor stage analyses were performed to assess the clinical associations. In addition, mucin 4 (MUC4) mRNA expression levels were measured in patient blood and tumor samples. According to the correlation analyses of four genes co-expressed, potential biological processes were identified. MUC4 was identified to be associated with H. pylori infection, and its levels were significantly upregulated in PC samples compared with those in normal samples in TCGA dataset, the PC cell line and patient tissue samples. H. pylori infection was also associated with MUC4 expression in patients' blood and tissue samples. In conclusion, the results of the present study revealed a potentially pathogenic role of MUC4 in H. pylori infection-associated PC. Thus, the tumorigenesis and metastasis of PC may be prevented by treating the H. pylori infection or using MUC4 antagonists.

HELLS, a chromatin remodeler is highly expressed in pancreatic cancer and downregulation of it impairs tumor growth and sensitizes to cisplatin by reexpressing the tumor suppressor TGFBR3.

Pancreatic cancer (PC) is the most malignant cancer type in the digestive system with a poor prognosis. Chemotherapy such as cisplatin is the last chance for PC patients diagnosed with advanced or metastatic disease. Obtaining a deep understanding of the molecular mechanism underlying PC tumorigenesis and identifying optimal biomarkers to estimate chemotherapy sensitivity are essential for PC treatment. The chromatin remodeler HELLS was found to regulate various tumor suppressors through an epigenetic pathway in several cancers. We analyzed HELLS expression in clinical samples by Western blotting and immunohistochemical staining. Next, we identified the variation in tumor growth and cisplatin sensitivity after knockdown of HELLS and explored the downstream mediators of HELLS in PC via RNA‐seq, chromatin immunoprecipitation, and gain‐ and loss‐of‐function assays. We found that HELLS is upregulated in PC tissues and correlates with advanced clinical stage and a poor prognosis, and the knockdown of HELLS leads to tumor growth arrest and increased sensitivity to cisplatin. Mechanistically, the tumor suppressor TGFBR3 is markedly reexpressed after HELLS knockdown; conversely, compromising TGFBR3 rescues HELLS knockdown‐mediated effects in PC cells. Thus, our data provide evidence that HELLS can serve as a potential oncogene and suitable biomarker to evaluate chemotherapy sensitivity via epigenetically silencing the tumor suppressor TGFBR3 in PC.

Hsa_circ_0000069 Knockdown Inhibits Tumorigenesis and Exosomes with Downregulated hsa_circ_0000069 Suppress Malignant Transformation via Inhibition of STIL in Pancreatic Cancer.

BackgroundCircular RNAs (circRNAs) play an important role in the tumorigenesis of pancreatic cancer. However, the expression profiles and roles of circRNAs in pancreatic cancer remain largely unknown.MethodsTo identify differentially expressed circRNAs (DEcircRNAs) between pancreatic cancer and matched normal tissues, bioinformatics analysis was performed. Hsa_circ_0000069 was identified by 0.bioinformatics analysis. In addition, the level of hsa_circ_0000069 in pancreatic cancer tissues and cell lines, and pancreatic cancer cell-derived exosomes were assessed using RT-qPCR assay.ResultsThe expression of hsa_circ_0000069 was markedly upregulated in pancreatic cancer tissues and cell lines. SCL/TAL1 interrupting locus (STIL) is the parent gene for hsa_circ_0000069, and its high expression was related to poor overall survival in patients with pancreatic cancer. In addition, downregulation of hsa_circ_0000069 markedly suppressed STIL expression, induced the apoptosis and cell cycle arrest, and inhibited the proliferation, migration and invasion in pancreatic cancer cells. Moreover, hsa_circ_0000069 knockdown inhibited the growth of xenograft pancreatic cancer tumors in vivo. Furthermore, human pancreatic duct epithelial cells (HPDE) are capable of internalizing SW1990 cell-derived exosomes, allowing the transfer of hsa_circ_0000069. Significantly, SW1990 cell-derived exosomes promoted the proliferation, migration and cell cycle progression of HPDE cells, whereas exosomes with downregulated hsa_circ_0000069 suppressed the proliferation, migration and cell cycle progression of HPDE cells, by suppressing STIL expression.ConclusionOur results suggest that hsa_circ_0000069 knockdown could inhibit pancreatic cancer tumorigenesis and exosomes with downregulated hsa_circ_0000069 could suppress HPDE cell malignant transformation. Collectively, hsa_circ_0000069 might be a therapeutic target for the treatment of pancreatic cancer.