Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.

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NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Feng Guo ◽

Yingke Zhou ◽

Hui Guo ◽

Dianyun Ren ◽

Xin Jin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Transcriptional Activation ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Gene Sets ◽

And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

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Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210201095613 ◽

2021 ◽

Vol 21 ◽

Author(s):

Huiming Chen ◽

Junfeng Zhao ◽

Ningning Jiang ◽

Zheng Wang ◽

Chang Liu

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Precancerous Lesions ◽

Clinical Specimen ◽

Ductal Adenocarcinoma ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

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Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

Integrative Cancer Therapies ◽

10.1177/1534735418794884 ◽

2018 ◽

Vol 17 (4) ◽

pp. 1016-1019 ◽

Cited By ~ 14

Author(s):

Chao Qu ◽

Qing Wang ◽

Zhiqiang Meng ◽

Peng Wang

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Stroma ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Therapeutic Effects ◽

Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

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CCL28 Downregulation Attenuates Pancreatic Cancer Progression Through Tumor Cell-Intrinsic and -Extrinsic Mechanisms

Technology in Cancer Research & Treatment ◽

10.1177/15330338211068958 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110689

Author(s):

Jingjing Yan ◽

Pengkun Yuan ◽

Liming Gui ◽

Zhixue Wang ◽

Pan Yin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cell ◽

Cancer Progression ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Suppressor Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Syngeneic Mouse Model

C-C motif chemokine ligand 28 (CCL28) has been reported to be pro-tumoral in several cancer types. However, the role of CCL28 in pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. CCL28 mRNA expression in tumors from PDAC patients was found to be elevated as compared to normal pancreas. CCL28 expression was also negatively correlated with overall survival (OS) in pancreatic cancer patients. Our in vitro experiments showed that CCL28 knockdown impairs the proliferation of mouse pancreatic cancer cell line PAN02. Moreover, in both immunocompetent syngeneic mice and immunodeficient NOD-SCID mice, CCL28 deficiency significantly attenuated the growth of subcutaneous PAN02 tumors. In syngeneic mouse model, CCL28 downregulation remodeled the pancreatic tumor microenvironment by suppressing the infiltration of both regulatory T (Treg) cells, myeloid-derived suppressor cells, and activated pancreatic stellate cells, and upregulating the expression of lymphocyte cytotoxic proteins including perforin and granzyme B. In conclusion, our work demonstrates that CCL28 is a potential target for pancreatic cancer treatment and CCL28 blockade could inhibit tumor growth through both tumor-cell-intrinsic and extrinsic mechanisms.

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Identification of FEZ2 as a potential oncogene in pancreatic ductal adenocarcinoma

PeerJ ◽

10.7717/peerj.12736 ◽

2022 ◽

Vol 9 ◽

pp. e12736

Author(s):

Chaozhi Yang ◽

Xuebing Wang ◽

Chenjie Qiu ◽

Ziruo Zheng ◽

Kai Lin ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Poor Prognosis ◽

Malignant Tumors ◽

Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Pathway Enrichment Analysis ◽

Conserved Gene

Pancreatic ductal adenocarcinoma (PDAC) is one of the common malignant tumors with high lethal rate and poor prognosis. Dysregulation of many genes have been reported to be involved in the occurrence and development of PDAC. However, as a highly conserved gene in eukaryotes, the role of Fasciculation and Elongation protein Zeta 2 (FEZ2) in pancreatic cancer progression is not clear. In this study, we identified the oncogenic effect of FEZ2 on PDAC. By mining of The Cancer Genome Atlas (TCGA) database, we found that FEZ2 was upregulated in PDAC tissues and FEZ2 expression was negatively regulated by its methylation. Moreover, high expression and low methylation of FEZ2 correlated with poor prognosis in PDAC patients. Besides, we found that FEZ2 could promote PDAC cells proliferation, migration and 5-FU resistance in vitro. Furthermore, Gene pathway enrichment analysis demonstrated a positive correlation between Wnt signaling activation and FEZ2 expression in PDAC patients. Western blot showed that FEZ2 knockdown significantly suppressed β-catenin expression. Collectively, our finding revealed that FEZ2 functioned as a potential oncogene on PDAC progression and migration, and the expression of FEZ2 had guidance value for the treatment and chemotherapy program of PDAC patients.

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Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

10.21203/rs.3.rs-95055/v1 ◽

2020 ◽

Author(s):

Qing Hua ◽

Tianjiao Li ◽

Yixuan Liu ◽

Xuefang Shen ◽

Xiaoyan Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Poor Prognosis ◽

Disease Free Survival ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. Results: KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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

Cell Death and Disease ◽

10.1038/s41419-020-03316-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jie Wang ◽

Zhiwei He ◽

Jian Xu ◽

Peng Chen ◽

Jianxin Jiang

Keyword(s):

Pancreatic Cancer ◽

Cell Growth ◽

Cell Lines ◽

Cancer Progression ◽

Noncoding Rna ◽

Epithelial Mesenchymal Transition ◽

Loss Of Function ◽

Mesenchymal Transition

AbstractAn 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.

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Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner

Clinical Epigenetics ◽

10.1186/s13148-021-01016-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Hongzhen Li ◽

Chunyan Peng ◽

Chenhui Zhu ◽

Shuang Nie ◽

Xuetian Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Nadph Oxidase ◽

Western Blot ◽

Cancer Progression ◽

Histone Methylation ◽

Invasion And Metastasis ◽

Independent Manner ◽

Nadph Oxidase 4

Abstract Background Hypoxia is a characteristic of the tumor microenvironments within pancreatic cancer (PC), which has been linked to its malignancy. Recently, hypoxia has been reported to regulate the activity of important carcinogenic pathways by changing the status of histone modification. NOX4, a member of NADPH oxidase (NOX), has been found to be activated by hypoxia and promote cancer progression in several cancers. But whether it is involved in the epigenetic changes of tumor cells induced by hypoxia is still unclear, and its biological roles in PC also need to be explored. Methods A hypoxic-related gene signature and its associated pathways in PC were identified by analyzing the pancreatic cancer gene expression data from GEO and TCGA database. Candidate downstream gene (NOX4), responding to hypoxia, was validated by RT-PCR and western blot. Then, we evaluated the relationship between NOX4 expression and clinicopathologic parameters in 56 PC patients from our center. In vitro and in vivo assays were preformed to explore the phenotype of NOX4 in PC. Immunofluorescence, western blot and chromatin immunoprecipitation assays were further applied to search for a detailed mechanism. Results We quantified hypoxia and developed a hypoxia signature, which was associated with worse prognosis and elevated malignant potential in PC. Furthermore, we found that NADPH oxidase 4 (NOX4), which was induced by hypoxia and upregulated in PC in a HIF1A-independent manner, caused inactivation of lysine demethylase 5A (KDM5A), increased the methylation modification of histone H3 and regulated the transcription of EMT-associated gene_ snail family transcriptional repressor 1 (SNAIL1). This served to promote the invasion and metastasis of PC. NOX4 deficiency repressed hypoxia-induced EMT, reduced expression of H3K4ME3 and impaired the invasion and metastasis of PC cells; however, knockdown of KDM5A reversed the poor expression of H3KEME3 induced by NOX4 deficiency, thereby promoting EMT. Conclusions This study highlights the prognostic role of hypoxia-related genes in PC and strong correlation with EMT pathway. Our results also creatively discovered that NOX4 was an essential mediator for hypoxia-induced histone methylation modification and EMT in PC cells.

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GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08898-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jung Hyun Jo ◽

Sun A Kim ◽

Jeong Hoon Lee ◽

Yu Rang Park ◽

Chanyang Kim ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Biomarker Discovery ◽

Disease Free Survival ◽

Tumor Formation ◽

Ductal Adenocarcinoma ◽

Curative Surgery ◽

In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

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SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

10.1101/2021.12.10.472112 ◽

2021 ◽

Author(s):

Scott B Biering ◽

Francielle Tramontini Gomes de Sousa ◽

Laurentia V. Tjang ◽

Felix Pahmeier ◽

Richard Ruan ◽

...

Keyword(s):

Transcriptional Response ◽

Barrier Dysfunction ◽

Vascular Leak ◽

Endothelial Barrier Dysfunction ◽

Mechanistic Insight ◽

Starting Point ◽

Signaling Axis ◽

Insight Into

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.

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