Dataset Information

Pancreatic Cancer Cell-Derived Exosomes Promote Lymphangiogenesis by Downregulating ABHD11-AS1 Expression.

ABSTRACT: Research on pancreatic cancer microbiomes has attracted attention in recent years. The current view is that enriched microbial communities in pancreatic cancer tissues may affect pancreatic cancer metastasis, including lymph node (LN) metastasis. Similar to carriers of genetic information between cells, such as DNA, mRNA, protein, and non-coding RNA, exosomes are of great importance in early LN metastasis in tumors, including pancreatic cancer. Our previous study showed that the long non-coding RNA ABHD11-AS1 was highly expressed in tissues of patients with pancreatic cancer, and was correlated with patient survival time. However, the role of ABHD11-AS1 in pancreatic cancer LN metastasis has rarely been studied. Hence, in this paper we confirmed that exosomes derived from pancreatic cancer cells could promote lymphangiogenesis in vitro and in vivo, and that the mechanism was related to the downregulation of ABHD11-AS1 expression in lymphatic endothelial cells, and to the enhancement of their ability to proliferate, migrate, and form tubes. These findings preliminarily show a new mechanism by which pancreatic cancer cells regulate peripheral lymphangiogenesis, providing a new therapeutic strategy for inhibiting LN metastasis in pancreatic cancer.

SUBMITTER: Zhou X

PROVIDER: S-EPMC9562033 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Pancreatic Cancer Cell-Derived Exosomes Promote Lymphangiogenesis by Downregulating ABHD11-AS1 Expression.

Zhou Xulin X Zhong Fengyun F Yan Yongmin Y Wu Sihui S Wang Huizhi H Liu Junqiang J Li Feifan F Cui Dawei D Xu Min M

Cancers 20220923 19

Research on pancreatic cancer microbiomes has attracted attention in recent years. The current view is that enriched microbial communities in pancreatic cancer tissues may affect pancreatic cancer metastasis, including lymph node (LN) metastasis. Similar to carriers of genetic information between cells, such as DNA, mRNA, protein, and non-coding RNA, exosomes are of great importance in early LN metastasis in tumors, including pancreatic cancer. Our previous study showed that the long non-coding ...[more]

PMID: 36230535

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Project description:PurposePancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion.Experimental methodsWe characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown.ResultsExosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.ConclusionsPancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.

Project description:BackgroundLuminal breast cancer (BC) is the most frequent subtype accounting for more than 70% of BC. LncRNAs, a class of non-coding RNAs with more than 200 nucleotides, are involved in a variety of cellular processes and biological functions. Abberant expression is related to the development of various cancers, such as breast cancer. LINC01133, ZEB1-AS1, and ABHD11-AS1 were reported to be dysregulated in different cancers. However, their expression level in luminal BC remains poorly known. The aim of the present study was to evaluate the potential roles of these lncRNAs in BC, especially in luminal subtypes.MethodsA comprehensive analysis was performed using the Lnc2Cancer database to identify novel cancer-associated lncRNA candidates. After conducting a literature review, three novel lncRNAs named LINC01133, ZEB1-AS1, and ABHD11-AS1 were chosen as target genes of the present study. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to evaluate the expression level of the mentioned lncRNAs in both luminal BC tissues and cell lines. Then, the correlation of the three mentioned lncRNAs expression with clinicopathological characteristics of the patients was studied. Moreover, several datasets were used to discover the potential roles and functions of LINC01133, ZEB1-AS1 and ABHD11-AS1 in luminal subtype of BC.ResultsAccording to the qRT-PCR assay, the expression levels of LINC01133 and ZEB1-AS1 were decreased in luminal BC tissues and cell lines. On the other hand, ABHD11-AS1 was upregulated in the above-mentioned samples. The expression levels of LINC01133, ZEB1-AS1, and ABHD11-AS1 were not associated with any of the clinical features. Also, the results obtained from the bioinformatics analyses were consistent with qRT-PCR data. Functional annotation of the co-expressed genes with the target lncRNAs, protein-protein interactions and significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways across luminal BC were also obtained using bioinformatics analysis.ConclusionsTaken together, our findings disclosed the dysregulation of LINC01133, ZEB1-AS1, and ABHD11-AS1 in luminal BC. It was revealed that LINC01133 and ZEB1-AS1 expression was significantly downregulated in luminal BC tissues and cell lines, while ABHD11-AS1 was upregulated considerably in the mentioned tissues and cell lines. Also, bioinformatics and systems biology analyses have helped to identify the possible role of these lncRNAs in luminal BC. However, further analysis is needed to confirm the current findings.

Dataset Information

Pancreatic Cancer Cell-Derived Exosomes Promote Lymphangiogenesis by Downregulating ABHD11-AS1 Expression.

Publications

Pancreatic Cancer Cell-Derived Exosomes Promote Lymphangiogenesis by Downregulating ABHD11-AS1 Expression.

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