Recent Advances on the Molecular Mechanisms Involved in Pancreatic Cancer Progression and Therapies

Abstract Background FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. Methods FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. Results FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. Conclusions Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

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Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

10.1101/2021.12.31.472823 ◽

2022 ◽

Author(s):

Claudia Tonelli ◽

Astrid Deschênes ◽

Melissa A. Yao ◽

Youngkyu Park ◽

David A. Tuveson

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Treatment Options ◽

Intraepithelial Neoplasia ◽

Ductal Adenocarcinoma ◽

Wild Type

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

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SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

Cell Death Discovery ◽

10.1038/s41420-021-00779-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhiping Fu ◽

Xing Liang ◽

Ligang Shi ◽

Liang Tang ◽

Danlei Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Hormone Secretion ◽

Migration And Invasion ◽

Dependent Manner ◽

Orphan Nuclear Receptor

AbstractPancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

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ELK1 Enhances Pancreatic Cancer Progression Via LGMN and Correlates with Poor Prognosis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.764900 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qiang Yan ◽

Chenming Ni ◽

Yingying Lin ◽

Xu Sun ◽

Zhenhua Shen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Clinical Stage ◽

Pancreatic Cancer Cells ◽

Degree Of Differentiation

Pancreatic cancer is one of the most lethal cancers and its prognosis is extremely poor. Clarification of molecular mechanisms and identification of prognostic biomarkers are urgently needed. Though we previously found that LGMN was involved in pancreatic carcinoma progression, the upstream regulation of LGMN remains unknown. We used reliable software to search for the potential transcription factors that may be related with LGMN transcription, we found that ELK1 could be a new regulator of LGMN transcription that binded directly to the LGMN promoter. Moreover, knocking down of ELK1 reduced pancreatic cancer cells proliferation, invasion and survival, while LGMN restored the malignancy of pancreatic cancer in vitro and in vivo. Overexpression of ELK1 further increased cancer cells proliferation, invasion and survival. Clinically, ELK1 and LGMN were positively correlated with clinical stage, degree of differentiation and Lymph node infiltration. ELK1 and LGMN were identified as independent prognostic factors for overall survival. The patients with low expression of ELK1/LGMN survived an average of 29.65 months, whereas those with high expression of ELK1/LGMN survived an average of 16.67 months. In conclusive, our results revealed a new mechanism by which ELK1 promoted the progression of pancreatic cancer via LGMN and conferred poor prognosis.

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MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators

BMC Cancer ◽

10.1186/s12885-019-6284-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 14

Author(s):

Afra Z. Daoud ◽

Eoghan J. Mulholland ◽

Grace Cole ◽

Helen O. McCarthy

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Target Prediction ◽

Pancreatic Disease ◽

Response To Therapy ◽

Wide Range ◽

Mirna Expression Profiles ◽

Novel Therapeutic Strategies

Abstract A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered. Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects. Graphical abstract

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Targeting hypoxic tumor microenvironment in pancreatic cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-020-01030-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jinxin Tao ◽

Gang Yang ◽

Wenchuan Zhou ◽

Jiangdong Qiu ◽

Guangyu Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Stromal Cells ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Metabolic Reprogramming ◽

Normal Tissues ◽

Innovative Therapies ◽

Hypoxic Tumor ◽

Resistance To Chemotherapy

AbstractAttributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

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Aberrantly DNA Methylated-Differentially Expressed Genes in Pancreatic Cancer Through an Integrated Bioinformatics Approach

Frontiers in Genetics ◽

10.3389/fgene.2021.583568 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haifeng Sun ◽

Rui Xin ◽

Changjun Zheng ◽

Ge Huang

Keyword(s):

Pancreatic Cancer ◽

Differentially Expressed Genes ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cox Model ◽

Cancer Prognosis ◽

Differentially Expressed ◽

Pathway Enrichment Analysis ◽

Sequencing Data ◽

Differentially Methylated Genes

Pancreatic cancer remains one of the chief contributors to cancer related deaths on a global scale, with its diagnosis often associated with poor prognosis and high mortality. Accumulating literature continues to highlight the role of aberrant DNA methylation in relation to pancreatic cancer progression. Integrated bioinformatics approaches in the characterization of methylated-differentially expressed genes (MeDEGs) in pancreatic cancer were employed to enhance our understanding of the potential underlying molecular mechanisms of this cancer. We initially identified differentially expressed genes (DEGs) between 178 pancreatic cancer samples and 4 normal samples and differentially methylated genes (DMGs) based on 185 pancreatic cancer samples as well as 10 normal samples by analyzing RNA sequencing data in the TCGA database. Eventually, 31 MeDEGs including 5 hypomethylated/upregulated genes and 26 hypermethylated/downregulated genes were identified. Univariate Cox model and Kaplan–Meier method revealed that, among 31 MeDEGs, 5 hypermethylated/downregulated genes (ZNF804A, ZFP82, TRIM58, SOX17, and C12orf42) were correlated with poor survival of patients with pancreatic cancer. KEGG pathway enrichment analysis by GSEA 3.0 and the protein–protein interaction (PPI) network revealed that these 5 MeDEGs were enriched in numerous cancer-related pathways in addition to interacting with each other, highlighting a significant role in the development of pancreatic cancer. Taken together, the key findings of the current study demonstrate that ZNF804A, ZFP82, TRIM58, SOX17, and C12orf42 are hypermethylated/downregulated genes in pancreatic cancer and may be associated, through their modulation of specific pathways, with unfavorable pancreatic cancer prognosis.

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MIB1 Upregulates IQGAP1 and Promotes Pancreatic Cancer Progression by inducing ST7 Degradation

10.21203/rs.3.rs-76668/v1 ◽

2020 ◽

Author(s):

Tao Liu ◽

Bin Zhang ◽

xin jin ◽

Xiang Cheng

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Western Blotting ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

The Relationship

Abstract BackgroundPancreatic cancer is a highly heterogeneous and has a poor prognosis. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient survival. Although the E3 ubiquitin ligase mind bomb 1 (MIB1) is involved in cancer cell proliferation and is often overexpressed in pancreatic cancer, the role of MIB1 in pancreatic cancer progression remains unclear.Methods The relationship of MIB1 with the clinicopathological features of pancreatic tumors was bioinformatically investigated in different datasets. The protein levels of MIB1 and ST7 were assessed by Western blotting and immunohistochemistry. The role of MIB1 and ST7 in pancreatic cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between MIB1 and ST7 was investigated by co-immunoprecipitation. The relationship between MIB1, ST7, and IQGAP1 levels was explored by Western blotting and quantitative real-time PCR.ResultsMIB1 expression was elevated in pancreatic cancer tissues, and its expression levels were associated with unfavorable prognosis. MIB1 overexpression enhanced pancreatic cancer proliferation and invasion in vitro and in vivo. We identified ST7 as a novel MIB1 target for proteasomal degradation. Further, we found that ST7 suppressed tumor growth by downregulating IQGAP1 in pancreatic cancer cells.ConclusionsThese data suggest that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation. ST7 suppresses tumor growth by downregulating IQGAP1 in pancreatic cancer cells. Therefore, the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may improve the survival of pancreatic cancer patients.

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