Malignant Progression Of Pancreatic Cancer Research Articles

Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer

BackgroundPancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PurposeTo investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. MethodsPancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. ResultsMoracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. ConclusionMoracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.

CCNI2 promotes pancreatic cancer through PI3K/AKT signaling pathway.

Globally, pancreatic cancer is recognized as one of the deadliest malignancies that lacks effective targeted therapies. This study aims to explore the role of cyclin I-like protein (CCNI2), a homolog of cyclin I (CCNI), in the progression of pancreatic cancer, thereby providing a theoretical basis for its treatment. Firstly, the expression of CCNI2 in pancreatic cancer tissues was determined through immunohistochemical staining. The biological role of CCNI2 in pancreatic cancer cells was further assessed using both in vitro and in vivo loss/gain-of-function assays. Our data revealed that CCNI2 expression was abnormally elevated in pancreatic cancer, and clinically, increased CCNI2 expression generally correlated with reduced overall survival. Functionally, CCNI2 contributed to the malignant progression of pancreatic cancer by promoting the proliferation and migration of tumor cells. Consistently, in vivo experiments verified that CCNI2 knockdown impaired the tumorigenic ability of pancreatic cancer cells. Moreover, the addition of phosphatidylinositol 3-kinase (PI3K) inhibitors could partially reverse the promoting effect of CCNI2 on the malignant phenotypes of pancreatic cancer cells. CCNI2 promoted pancreatic cancer through PI3K/protein kinase B (AKT) signaling pathway, indicating its potential as a prognostic marker and therapeutic target for pancreatic cancer.

Abstract A030: Fusion between macrophages and cancer cells up-regulates signal regulatory protein pathway and contributes to malignant progression of pancreatic cancer after radiation

Abstract Introduction: Fusion between tumor cells with leukocytes contributes to tumor heterogeneity, resulting in tumorigenesis, metastasis, and treatment resistance. Recent studies demonstrate that an inflammatory microenvironment enhances tumor-macrophage fusion. We hypothesize that tumor-macrophage fusion hybrids contribute to radiation induced pancreatic cancer progression. Materials and Methods: Tumor tissues of female patients receiving previous bone marrow transplantation (BMT) from male donors due to leukemia/lymphoma were collected for Y chromosome and immunofluorescence study. Murine subcutaneous tumor models of cre-loxP or dual fluorescence system were established to demonstrate fusion between Pan02, a murine pancreatic adenocarcinoma cell line, and stromal cells of ROSA (Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo/Jnarl) mice with or without local radiation exposure. KC (pdx-1-cre-KrasLSL-G12D) mice, were given whole body irradiation followed by BMT from ROSA mice to measure fusion between pancreatic cancer and hematopoietic cells. Liposomal chlodronate, a macrophage depleting agent, and immunofluorescence staining of fusion hybrids in ROSA mice tumors were used to demonstrate macrophage as a fusion partner. Fusion hybrid clones of murine/human pancreatic adenocarcinoma cells with macrophages were selected from co-culture and sorting followed by studies including ploidy, clonogenicity, migration and radio-sensitivity. Affymetrix microarray analysis was used to find differentially expressed genes of fusion hybrids. Results: Fusion phenomenon was demonstrated by showing colocalization of Y chromosomes with epithelial markers in cancer tissues from female patients receiving prior BMT from male donors. Fusion hybrids were found in pancreas tumors of KC mice after BMT from ROSA mice. Fusion hybrids within tumors increased by time, three folds within 6 weeks; and 2.5 folds after 20Gy radiation exposure. Liposomal clodronate reduced fusion hybrids and tumor growth. Immunofluorescence stain of tumor tissues demonstrated CD11b(+) macrophage to be the major fusion partner. Purified Fusion hybrids showed enhanced migration, proliferation, aneuploidy and radio-resistance. Model based gene analysis of microarray study disclosed signal regulatory protein (SIRP) signal pathway was significantly upregulated in fusion hybrids. Upregulated SIRP signal molecules, including DAP12, PyK2, were validated by immunoblots. Silencing DAP12 in myeloid cells from human peripheral blood showed decreased fusion rate with Panc-1 cells. DAP12mRNA depletion in Panc-1 fusion hybrids disclosed enhanced radio-sensitivity. Defactinib (VS6063), a PyK2 inhibitor, reduced fusion phenomenon and suppressed pancreatic tumor growth of mice after local radiation. Conclusions: Fusion between pancreatic cancer cells and macrophages contribute to radiation enhanced malignant progression of pancreatic cancer. SIRP signal pathway is a potential target to disrupt fusion phenomenon and ameliorate pancreatic cancer progression after radiation. Citation Format: Hui Ju Ch'ang, Yi-Chih Tsai, Ting Wei Li, Rui-Jun Liu, Tze-Sing Huang, Sse-Pei Wan, Su-Liang Chen, Shih-Sheng Jiang. Fusion between macrophages and cancer cells up-regulates signal regulatory protein pathway and contributes to malignant progression of pancreatic cancer after radiation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A030.

Aberrant expression of CKS2 induced by ELK1 contributes to malignant progression of pancreatic cancer.

Cyclin-dependent kinase subunit 2 (CKS2) has been reported to promote various malignancies. This study investigated the functional role of CKS2 in pancreatic cancer (PC). An analysis of abnormally expressed genes and their prognostic value for PC was performed by using the Gene Expression Profiling Interactive Analysis (GEPIA) database and performing immunohistochemical staining on 64 samples of tumor tissue. CCK-8 assays, EdU staining, colony formation assays, flow cytometry, and a xenograft tumor model were used to analyze the biological function of CKS2 in PC. Our results revealed that CKS2 was expressed at significantly higher levels in PC tissues than in adjacent normal tissues, and a high level of CKS2 expression was associated with a poor prognosis for patients with PC. Moreover, functional assays revealed that CKS2 knockdown suppressed cell proliferation, induced cell cycle S phase, G2/M phase arrest, and apoptosis in vitro, and also reduced tumor growth in vivo. In addition, CKS2 knockdown increased the levels of Bax, caspase-3, P53, P21, and GADD45α expression, but decreased Bcl-2, Cyclin B1, CDK1, Cyclin A, and Cdc25C expression. CKS2 overexpression produced the opposite effects of CKS2 knockdown. Furthermore, we found that ELK1 protein regulated transcription of the CKS2 gene. In conclusion, our findings suggest that CKS2 expression is regulated by ELK1, which could possibly serve as prognostic indicator and therapeutic target for PC.

The DEAD-box RNA helicase, DDX60, Suppresses immunotherapy and promotes malignant progression of pancreatic cancer

Excessive proliferation, invasion, metastasis, and immune resistance in pancreatic cancer (PC) makes it one of the most lethal malignant tumors. Recently, DDX60 was found to be involved in the development of various tumors and in immunotherapy. Therefore, we aimed to investigate whether DDX60 is a new factor involved in PC immunotherapy. The DDX60 mRNA was screened using transcriptome sequencing (RNA-seq). The Cox and survival analysis of DDX60 was performed using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, clinical and immune infiltration data in the databases were analyzed and plotted using the R language. Clinical samples and in vitro experiments were used to determine the molecular evolution of DDX60 during PC progression. We found that DDX60 was upregulated in PC tissues (P value = 0.0083) and was associated with poor prognosis and short survival time of patients with PC. Results of Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set variation analyses showed that viral defense, tumor, and immune-related pathways were significantly enriched in samples with high DDX60 expression. The Pearson correlation test demonstrated that DDX60 expression correlated strongly with immune checkpoint and immune system-related metagene clusters. Our results indicated that DDX60 promoted cell proliferation, migration, and invasion and was related to poor prognosis and immune resistance. Therefore, DDX60 may be a promising novel target for PC immunotherapy.

METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5

BackgroundPancreatic cancer belongs to lethal cancer with limited efficient treatment currently, and its main cause of death is rapid tumor growth and early metastasis. N6-methyladenosine (m6A) modification is a new method of epigenetic gene regulation involved in tumor progression, in which methyltransferase-like 3(METTL3) is the sole catalytic subunit. However, the role of METTL3 in pancreatic cancer remains to be explored. Methodsm6A level was measured using MeRIP assay, and RT-qPCR and western blot were applied to determine mRNA and protein expression, respectively. Cellular behaviors were detected using CCK-8, EdU, wound healing and transwell assays. Xenograft assays were conducted to further verify the roles of METTL3 in pancreatic cancer. ResultsMETTL3 was highly expressed in pancreatic cancer. However, downregulation of METTL3 restrained the viability, migration and invasion of pancreatic cancer cells. Moreover, E2F5 was found to be positively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of pancreatic cancer cells were overturned by overexpression of E2F5. Silencing METTL3 resulted in the decreased stability of E2F5 by methylating E2F5. ConclusionsIn conclusion, METTL3 can promote the malignant progression of pancreatic cancer by modifying E2F5 through m6A methylation to promote its stability.

Research advances of N6-methyladenosine in diagnosis and therapy of pancreatic cancer.

BackgroundN6‐methyladenosine (m6A) is the addition of a methyl group on the N6 position of adenosine and is the most prevalent and abundant epigenetic modification in eukaryote mRNA. m6A marks are added to mRNA by the m6A methyltransferase complex (“writers”), removed by m6A demethylases (“erasers”), and recognized by m6A‐binding proteins (“readers”). Recent evidence has shown that the m6A modification plays a crucial role in the pathogenic mechanism and malignant progression of pancreatic cancer, with roles in cell survival, proliferation, migration, invasion, tumor metastasis, and drug resistance.MethodsLiterature was searched in Pubmed and Web of Science for the following keywords: “N6‐methyladenosine”, “pancreatic cancer”, “epigenetic modification”, “immunotherapy”.ResultsAmong classical m6A regulators, while METTL3, METTL14, WTAP, FTO, YTHDF2, IGF2BP1–3, hnRNPC, and NKAP are upregulated in pancreatic cancer, METTL16 and ALKBH5 are downregulated in pancreatic cancer. m6A modification has been investigated in pancreatic cancer therapy.ConclusionDysregulated m6A and its related factors in pancreatic cancer cells and patients indicate their potential values as novel biomarkers in pancreatic cancer diagnosis and targeted therapy.

Heterogeneous cancer-associated fibroblasts: A new perspective for understanding immunosuppression in pancreatic cancer.

Immunotherapy has shown promising efficacy in the treatment of a wide range of cancers; however, it has had little effect on pancreatic cancer. Cancer-associated fibroblasts (CAFs), the predominant mesenchymal cells present in the pancreatic cancer microenvironment, are powerful supporters of the malignant progression of pancreatic cancer. CAFs can modify the microenvironment, establish a refuge to aid cancer cells in immune escape by secreting large amounts of extracellular matrix, and produce soluble cytokines and exosomal vesicles. Hence, CAFs are important contributors to the failure of immunotherapy. Current in-depth studies of CAFs have shown that CAFs are a heterogeneous population of mesenchymal cells; therefore, the functional complexity of their populations needs in-depth explorations in future studies. This review summarizes how heterogeneous CAFs help cancer cells achieve immune escape and suggests potential directions for using CAFs as targets to address immune escape.

Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis

Inflammatory molecules and exosomes are crucial for signal transduction between tumor-associated macrophages and tumor cells. IL-6, a key inflammatory molecule secreted by M2 macrophages after polarization, can mediate malignant progression of pancreatic cancer (PC). However, the functions and mechanisms of IL-6 and tumor-derived exosomes in tumor-associated macrophages and PC remain unclear. Transcriptome chip and quantitative reverse transcription PCR experiments indicated that FGD5-AS1 induced IL-6 and high FGD5-AS1 expression correlated with the poor prognosis in PC patients. RNA pulldown, mass spectrometry, and dual luciferase reporter assays were used to identify the mechanism of exosomal FGD5-AS1 in promoting PC progression and M2 macrophage polarization. FGD5-AS1 exerted cancer-promoting functions when co-cultured with M2 macrophages. PC-derived exosomal FGD5-AS1 stimulated M2 macrophage polarization by activating STAT3/NF-κB pathway. FGD5-AS1 interacts with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB. These data indicated that PC cells generate FGD5-AS1-rich exosomes, which cause M2 macrophage polarization to promote the malignant behaviors of PC cells. Targeting exosomal FGD5-AS1 may provide a potential diagnosis and treatment strategy for PC.

Solute Carrier Family 35 Member F2 Regulates Cisplatin Resistance and Promotes Malignant Progression of Pancreatic Cancer by Regulating RNA Binding Motif Protein 14.

We aimed to explore the role of Solute Carrier Family 35 Member F2 (SLC35F2) in pancreatic cancer (PCa) and to further study whether SLC35F2 regulates cisplatin resistance of PCa cells through the modulation of RNA binding motif protein 14 (RBM14) expression. SLC35F2 expression in 60 pairs of PCa tissues and adjacent ones was studied by RT-PCR analysis. Meanwhile, SLC35F2 expression levels in PCa cell lines were also evaluated by qPCR assay. In addition, SLC35F2 knockdown models were constructed in PCa cisplatin-resistant cells. Furthermore, we determined the interaction between SLC35F2 and RBM14 via luciferase assay. The findings of the present study demonstrated that SLC35F2 was significantly upregulated in PCa tissues. High level of SLC35F2 indicated higher incidence of metastasis and shorter survival rates. In vitro cell experiments revealed that knockdown of SLC35F2 suppressed cell invasion and metastasis capacity of cisplatin-resistant PCa cell lines PANC-1/DDP and CFPAC-1/DDP. It was also suggested that the key protein RBM14 in the SLC35F2 knockdown group was remarkably reduced. SLC35F2 can bind to RBM14 specifically. Overexpression of RBM14 partially reversed the effects of knockdown of SLC35F2 on the development of PCa. SLC35F2 expression in PCa tissues and cell lines is remarkably increased. In addition, it was also suggested that SLC35F2 may regulate cisplatin resistance of PCa cells through modulating RBM14 expression. In conclusion, it is conceivable from the study that SLC35F2 was remarkably upregulated in PCa and promoted the malignancy of PCa via regulating RBM14.

Retraction: MiRNA-107 enhances the malignant progression of pancreatic cancer by targeting TGFBR3.

Retraction: MiRNA-107 enhances the malignant progression of pancreatic cancer by targeting TGFBR3.

MiR-135b-5p is an oncogene in pancreatic cancer to regulate GPRC5A expression by targeting transcription factor KLF4

KLF4 is implicated in tumor progression of pancreatic cancer, but the molecular regulatory mechanism of KLF4 needs to be further specified. We aimed to probe molecular regulatory mechanism of KLF4 in malignant progression of pancreatic cancer. qRT-PCR or western blot was completed to test levels of predicted genes. Dual-luciferase and chromatin immunoprecipitation (ChIP) assays were designed to validate binding between genes. Cell viability and oncogenicity detection were used for in vitro and vivo functional assessment. KLF4 was a downstream target of miR-135b-5p. KLF4 could regulate GPRC5A level. MiR-135b-5p was notably increased in cancer cells, and overexpressing KLF4 functioned a tumor repressive role, which could be restored by miR-135b-5p. Besides, cell malignant phenotypes could be inhibited through reducing miR-135b-5p level, but they were restored by GPRC5A. Our results stressed that KLF4, as a vital target of miR-135b-5p, could influence promoter region of GPRC5A, thus affecting the malignant progression of pancreatic cancer.

HTR1D functions as a key target of HOXA10-AS/miR-340-3p axis to promote the malignant outcome of pancreatic cancer via PI3K-AKT signaling pathway

Competing endogenous RNAs (ceRNAs) are a newly discovered class of molecular regulators involved in many diseases, especially tumors. Therefore, exploration of the potential ceRNA regulatory network regarding the occurrence and development of pancreatic cancer will provide a new theoretical basis for its diagnosis and treatment. Based on the above background, we applied a bioinformatics approach to mine the public database The Cancer Genome Atlas (TCGA) and performed a series of subsequent molecular biology assays to confirm the hypothesis that HOXA10-AS/ miR-340-3p/HTR1D axis could modulate the malignant progression of pancreatic cancer. Here, our present study demonstrated that the expression level of HTR1D, positively correlated with the level of lncRNA HOXA10-AS and negatively associated with the level of miR-340-3p, was significantly increased in pancreatic cancer cell lines (PCs) compared with that in normal HPDE6-C7 cells. Knocking down HTR1D obviously inhibited the proliferation and migration of PCs and promoted apoptosis by upregulating p-AKT. Elevated miR-340-3p blocked the progression of pancreatic cancer by downregulating HTR1D. Lessened level of lncRNA HOXA10-AS reduced the sponging of miR-340-3p, resulting in an increase of miR-340-3p and a subsequent decrease of HTR1D to ultimately suppress the malignant biological behaviors of cancer. These data illustrated that the HOXA10-AS/miR-340-3p/HTR1D ceRNA axis acted a crucial part in the malignant biological behavior of pancreatic cancer in an AKT-dependent manner.

Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer.

Pancreatic cancer is associated with highly malignant tumors and poor prognosis due to strong therapeutic resistance. Accumulating evidence shows that activated pancreatic stellate cells (PSC) play an important role in the malignant progression of pancreatic cancer. In recent years, the rapid development of single-cell sequencing technology has facilitated the analysis of PSC population heterogeneity, allowing for the elucidation of the relationship between different subsets of cells with tumor development and therapeutic resistance. Researchers have identified two spatially separated, functionally complementary, and reversible subtypes, namely myofibroblastic and inflammatory PSC. Myofibroblastic PSC produce large amounts of pro-fibroproliferative collagen fibers, whereas inflammatory PSC express large amounts of inflammatory cytokines. These distinct cell subtypes cooperate to create a microenvironment suitable for cancer cell survival. Therefore, further understanding of the differentiation of PSC and their distinct functions will provide insight into more effective treatment options for pancreatic cancer patients.

CircRNF13 Promotes the Malignant Progression of Pancreatic Cancer through Targeting miR-139-5p/IGF1R Axis.

Background Mounting evidence has shown circular RNAs (circRNAs) play an important role in the initiation and progression of pancreatic cancer (PC). Meanwhile, circRNAs may serve as the biomarkers for the diagnosis, treatment, and prognosis of PC. Therefore, it is urgent to elucidate the function and underlying mechanism of circRNAs in the development of PC. Methods The Cancer-Specific CircRNA Database (CSCD), Circular RNA Interactome database (circinteractome database), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to verify the expression level of circRNF13 in PC cell lines. Fluorescence in situ hybridization (FISH) and RNase protection assay were used to detect the localization and structure of circRNF13. Then, cell functional experiments were employed to estimate the proliferated, migrated, and invasive abilities in PC. Furthermore, bioinformatic tools, luciferase dual reporter assay, and RT-qPCR were used to investigate the interaction among circRNF13, miR-139-5p, and IGF1R. Eventually, the rescue functional experiments were employed to confirm that circRNF13 targeted the miR-139-5p/IGF1R axis to participate in the development of PC. Results CircRNF13 was overexpressed in PC cell lines compared with the normal pancreatic duct cell line. Additionally, inhibition of circRNF13 impaired the proliferation, migration, and invasion of PC cells. CircRNF13 could serve as the molecular sponge of miR-139-5p to inhibit its association with IGF1R that eventually accelerated the malignant progression of PC. Conclusion CircRNF13 serves as a competitive endogenous RNA of IGF1R to inhibit the function of miR-139-5p that eventually reinforces the malignant phenotype of PC.

MicroRNA‑190bexpression predicts a good prognosis and attenuates the malignant progression of pancreatic cancer by targeting MEF2C and TCF4.

MicroRNAs (miRNAs/miRs) are key components of regulatory networks in cancer. Although miR-190b is an important tumor-related miRNA, its role in pancreatic cancer has not been extensively investigated. The aim of the present study was to examine the expression of miR-190b in pancreatic cancer cell lines and tissues and evaluate its effects on cancer progression. Reverse transcription-quantitative PCR (RT-qPCR) analysis was used to measure miR-190b expression levels in human pancreatic cancer cell lines and tissues, and the association between miR-190b expression and clinicopathological characteristics was assessed. An in vitro Transwell invasion assay and an in vivo metastasis formation assay were performed using pancreatic cancer cells. The effect of miR-190b on pancreatic cancer cell proliferation was evaluated using a Cell Counting Kit-8 assay based on an in vivo xenograft mouse model. The direct targets of miR-190b were predicted using bioinformatics tools and were validated through western blotting and luciferase reporter assays. Pancreatic cancer cell lines and tissues were found to express lower levels of miR-190b compared with normal cells and adjacent non-tumor tissues. Furthermore, high expression of miR-190b was found to be positively correlated with low T, N and American Joint Committee on Cancer classifications, and predicted a good prognosis. miR-190b was shown to exert suppressive effects on cancer cell proliferation, invasion and metastasis. In addition, it was also found that miR-190b directly targeted myocyte enhancer factor 2C (MEF2C) and transcription factor 4 (TCF4) in pancreatic cancer, thus serving as a tumor suppressor and a predictor of good prognosis in pancreatic cancer. The immunohistochemistry and RT-qPCR results indicated that the MEF2C and TCF4 expression levels were negatively correlated with the miR-190b expression levels. The findings of the present study highlight the value of miR-190b as a novel target candidate for pancreatic cancer diagnosis and therapy.

Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth

The nuclear receptor-binding SET domain 3 (NSD3) catalyzes methylation of histone H3 at lysine 36 (H3K36), and promotes malignant transformation and progression of human cancer. Its expression, potential functions and underlying mechanisms in pancreatic cancer are studied. Bioinformatics studies and results from local human tissues show that NSD3 is upregulated in human pancreatic cancer tissues, which is correlated with poor overall survival. In primary and established pancreatic cancer cells, NSD3 silencing (by shRNAs) or CRISPR/Cas9-induced NSD3 knockout potently inhibited cell proliferation, migration and invasion, while provoking cell cycle arrest and apoptosis. Conversely, ectopic expression of NSD3-T1232A mutation significantly accelerated proliferation, migration, and invasion of pancreatic cancer cells. H3K36 dimethylation, expression of NSD3-dependent genes (Prkaa2, Myc, Irgm1, Adam12, and Notch3), and mTOR activation (S6K1 phosphorylation) were largely inhibited by NSD3 silencing or knockout. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD3 shRNA potently inhibited pancreatic cancer xenograft growth in nude mice. These results suggest that elevated NSD3 could be an important driver for the malignant progression of pancreatic cancer.

MiRNA-107 enhances the malignant progression of pancreatic cancer by targeting TGFBR3.

BackgroundThe prognosis of pancreatic cancer (PC) is relatively dismal due to the lack of effective therapy. In this study, we explored the specific functions and molecular mechanisms of miR-107 to uncover effective therapeutic targets for PC.MethodThe miR-107 expression in PC cell lines was assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Besides, online bioinformatics analysis was adopted to predict the underlying targets of miR-107. Meanwhile, TCGA database was employed to explore the prognosis of PC patients. In addition, MTT and transwell assays were conducted to explore the PC cells’ biological functions.ResultMiR-107 was remarkably increased in PC cells which could promote the proliferation, invasion and migration of PC cells. In addition, miR-107 could directly down-regulate TGFBR3 expression through binding to TGFBR3 3’UTR. Survival analysis from TCGA suggested that PC patients with higher miR-107 expression was significantly involved in poorer prognosis.ConclusionWe concluded that miR-107 promoted proliferation, invasion and migration of PC cells via targeting TGFBR3, which may provide novel underlying therapeutic targets.

Long non-coding RNA PART1 predicts a poor prognosis and promotes the malignant progression of pancreatic cancer by sponging miR-122

Background and objectivesLong non-coding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) was previously shown to exert an oncogenic role in several human cancers. However, whether PART1 is associated with the malignant progression of pancreatic cancer remains unclear. In the current study, we aimed to identify the role and potential mechanism of PART1 in pancreatic cancer.MethodsqRT-PCR was applied to detect PART1 expression in 45 cases of pancreatic cancer patients. The chi-square test was performed to assess the association between PART1 expression and clinicopathologic features, and Kaplan-Meier method was applied to evaluate overall survival. In vitro CCK-8, transwell invasion, and flow cytometry assays were applied to detect the effects of PART1 on cell proliferation, invasion, and apoptosis, respectively. Luciferase reporter and RNA immunoprecipitation assays were used to identify the regulatory mechanism between PART1 and miR-122.ResultsPART1 expression was upregulated in pancreatic cancer tissues and cell lines. High PART1 expression was closely correlated with tumor size, T classification, clinical stage, and vascular invasion, and predicted a poor overall survival. PART1 knockdown significantly suppressed cell proliferation and invasion abilities of pancreatic cancer but promoted cell apoptosis. PART1 was found to serve as a molecular sponge of miR-122, and miR-122 inhibition partially reversed the inhibitory phenotypes of PART1 knockdown on pancreatic cancer cells.ConclusionsPART1 promotes the malignant progression of pancreatic cancer by sponging miR-122. The PART1/miR-122 axis might be a promising target for anticancer therapy in patients with pancreatic cancer.

MiR-4282 contributes to inhibit pancreatic cancer metastasis by negatively interacting with ABCB5.

To explore the regulatory mechanism of microRNA-4282 (miR-4282) on influencing pancreatic cancer progression by targeting ABCB5. MiR-4282 and ABCB5 levels in 58 cases of pancreatic cancer and paracancerous tissues were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The influences of miR-4282 on pathological indicators and prognosis in pancreatic cancer patients were analyzed. MiR-4282 overexpression model was established in PANC-1 and BxPC-3 cells by transfection of miR-4282 mimic. Transwell and wound healing assay were conducted to illustrate the role of miR-4282 in influencing cell functions of pancreatic cancer. Bioinformatics analysis and Dual-Luciferase reporter assay were carried out to ascertain the interaction between miR-4282 and ABCB5. MiR-4282 was downregulated in pancreatic cancer samples. Low level of miR-4282 predicted high incidences of lymphatic metastasis and distant metastasis, as well as poor prognosis in pancreatic cancer patients. Overexpression of miR-4282 remarkably inhibited migratory ability in PANC-1 and BxPC-3 cells. MiR-4282 was targeted by ABCB5 through specific binding sites. In pancreatic cancer tissues, ABCB5 level was negatively correlated to that of miR-4282. Overexpression of ABCB5 could abolish the inhibitory effects of overexpressed miR-4282 on the malignant progression of pancreatic cancer. MiR-4282 is able to inhibit the migratory ability in pancreatic cancer cells by negatively targeting ABCB5, which may become a promising pancreatic cancer biomarker.