Dataset Information

Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL.

ABSTRACT: Growth and differentiation factor 15 (GDF-15) has been studied as an important hallmark of cancer. However, the receptor of GDF-15 in pancreatic cancer cell remains unclear. Here, we investigated its biological effects in pancreatic ductal adenocarcinoma (PDAC). We found that aberrant GDF-15 expression positively correlated with poor survival of PDAC patients. GDF-15 protein enhanced tumor cell proliferation in two pancreatic cancer lines, AsPC-1 and BxPC-3. Knockdown GDF-15 attenuated its biological function in vitro and reduced PDAC cell tumorigenesis upon xenotransplantation into nude mice. Moreover, we identified that glial-derived neurotropic factor family receptor ?-like (GFRAL) was upregulated in PDAC tissues and positively correlated with GDF-15 expression. High GFRAL expression was significantly associated with poor survival in PDAC patients. Furthermore, we identified that the biological effects of GDF-15 are mediated by its receptor GFRAL which is present in PDAC cells. After overexpression GFRAL in pancreatic cancer cells, the effect of GDF-15 was significantly enhanced. Overall, our findings demonstrated that the GDF-15 secreted by PDAC cells, binds to GFRAL, itself localized in PDAC cells, to promote cancer cell growth and metastasis through the GDF-15/GFRAL signaling pathway.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC7746332 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL.

Zhao Zhiping Z Zhang Junfeng J Yin Liangyu L Yang Jiali J Zheng Yao Y Zhang Mengjie M Ni Bing B Wang Huaizhi H

Aging 20201117 22

Growth and differentiation factor 15 (GDF-15) has been studied as an important hallmark of cancer. However, the receptor of GDF-15 in pancreatic cancer cell remains unclear. Here, we investigated its biological effects in pancreatic ductal adenocarcinoma (PDAC). We found that aberrant GDF-15 expression positively correlated with poor survival of PDAC patients. GDF-15 protein enhanced tumor cell proliferation in two pancreatic cancer lines, AsPC-1 and BxPC-3. Knockdown GDF-15 attenuated its biolo ...[more]

PMID: 33201838

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Project description:Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

Project description:Background:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. The rapid progression of PDAC results in an advanced stage of patients when diagnosed. However, the dynamic molecular mechanism underlying PDAC progression remains far from clear. Methods:The microarray GSE62165 containing PDAC staging samples was obtained from Gene Expression Omnibus and the differentially expressed genes (DEGs) between normal tissue and PDAC of different stages were profiled using R software, respectively. The software program Short Time-series Expression Miner was applied to cluster, compare, and visualize gene expression differences between PDAC stages. Then, function annotation and pathway enrichment of DEGs were conducted by Database for Annotation Visualization and Integrated Discovery. Further, the Cytoscape plugin DyNetViewer was applied to construct the dynamic protein-protein interaction networks and to analyze different topological variation of nodes and clusters over time. The phosphosite markers of stage-specific protein kinases were predicted by PhosphoSitePlus database. Moreover, survival analysis of candidate genes and pathways was performed by Kaplan-Meier plotter. Finally, candidate genes were validated by immunohistochemistry in PDAC tissues. Results:Compared with normal tissues, the total DEGs number for each PDAC stage were 994 (stage I), 967 (stage IIa), 965 (stage IIb), 1027 (stage III), 925 (stage IV), respectively. The stage-course gene expression analysis showed that 30 distinct expressional models were clustered. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the up-regulated DEGs were commonly enriched in five fundamental pathways throughout five stages, including pathways in cancer, small cell lung cancer, ECM-receptor interaction, amoebiasis, focal adhesion. Except for amoebiasis, these pathways were associated with poor PDAC overall survival. Meanwhile, LAMA3, LAMB3, LAMC2, COL4A1 and FN1 were commonly shared by these five pathways and were unfavorable factors for prognosis. Furthermore, by constructing the stage-course dynamic protein interaction network, 45 functional molecular modules and 19 nodes were identified as featured regulators for all PDAC stages, among which the collagen family and integrins were considered as two main regulators for facilitating aggressive progression. Additionally, the clinical relevance analysis suggested that the stage IV featured nodes MLF1IP and ITGB4 were significantly correlated with shorter overall survival. Moreover, 15 stage-specific protein kinases were identified from the dynamic network and CHEK1 was particularly activated at stage IV. Experimental validation showed that MLF1IP, LAMA3 and LAMB3 were progressively increased from tumor initiation to progression. Conclusions:Our study provided a view for a better understanding of the dynamic landscape of molecular interaction networks during PDAC progression and offered potential targets for therapeutic intervention.

Dataset Information

Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL.

Publications

Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL.

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