Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy

Mortoglou, Maria; Tabin, Zoey Kathleen; Arısan, Elif Damla; Kocher, Hemant M.; Uysal-Onganer, Pinar

doi:10.1016/j.tranon.2021.101090

Cited by 25 publications

(19 citation statements)

References 291 publications

(183 reference statements)

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“…Due to the development of high-throughput sequencing technology and bioinformatics, circRNAs have attracted increasing attention in the noncoding RNA field and have been discovered and reported as critical regulators of various biological processes, including multiple cancers [ 27 , 28 ]. Currently, the roles of circRNAs in the progression of pancreatic cancer have been revealed in many studies [ 29 ]. Recently, our team reported that circBFAR promotes the progression of PDAC via the miR-34b-5p/MET/Akt axis and that circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer [ 20 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway

Zheng

Lin

et al. 2022

J Exp Clin Cancer Res

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Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by clusters of cancer cells surrounded by a dense desmoplastic stroma. However, little is known about stromal cell heterogeneity in the pancreatic tumor microenvironment. Methods We conducted circRNA profiling in primary fibroblasts by high-throughput sequencing and detected circCUL2 levels in PDAC tissues by qRT–PCR. We subsequently investigated the effect of circCUL2 on inflammatory cancer-associated fibroblast (iCAF) activation, heterogeneity and protumor activity by ELISA, flow cytometry, colony formation and transwell assays in vitro and by xenograft models in vivo. The regulatory effect of circCUL2 on miR-203a-3p/MyD88/IL6 was examined by RNA pulldown, FISH, and luciferase reporter assays. Results We identified that circCUL2 was specifically expressed in cancer-associated fibroblasts (CAFs) but not in cancer cells. Moreover, the enrichment of circCUL2 in tumor tissues was significantly correlated with the poor prognosis of PDAC patients. Upregulation of circCUL2 expression in normal fibroblasts (NFs) induced the iCAF phenotype, and then iCAFs promoted PDAC progression through IL6 secretion in vitro. Furthermore, circCUL2-transduced NFs promoted tumorigenesis and metastasis of PDAC cells in vivo, which was blocked by an anti-IL6 antibody. Mechanistically, circCUL2 functioned as a ceRNA and modulated the miR-203a-3p/MyD88/NF-κB/IL6 axis, thereby further activating the STAT3 signaling pathway in pancreatic cancer cells to induce PDAC progression. Conclusions We showed that the circCUL2/miR-203a-5p/MyD88/NF-κB/IL6 axis contributes to the induction of iCAFs and established a distinct fibroblast niche for PDAC progression, which could help the development of strategies that selectively target tumor-promoting CAFs in PDAC.

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Section: Discussionmentioning

confidence: 99%

circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway

Zheng

Lin

et al. 2022

J Exp Clin Cancer Res

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“…MiR-19a-3p was shown to be overexpressed in PDAC with a potential to be used as an early non-invasive diagnostic biomarker but also as a prognostic biomarker. Another study reported the role of miR-29a, miR29b, miR-103, and miR-320 as early diagnostic predictors of PDAC when upregulated [50].…”

Section: Diagnostic Biomarkersmentioning

confidence: 99%

Neoadjuvant Treatment for Pancreatic Adenocarcinoma: A False Promise or an Opportunity to Improve Outcome?

Khakoo

Petrillo

Salati

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) has an aggressive tumor biology and is associated with poor survival outcomes. Most patients present with metastatic or locally advanced disease. In the 10–20% of patients with upfront resectable disease, surgery offers the only chance of cure, with the addition of adjuvant chemotherapy representing an established standard of care for improving outcomes. Despite resection followed by adjuvant chemotherapy, at best, 3-year survival reaches 63.4%. Post-operative complications and poor performance mean that around 50% of the patients do not commence adjuvant chemotherapy, and a significant proportion do not complete the intended treatment course. These factors, along with the advantages of early treatment of micrometastatic disease, the ability to downstage tumors, and the increase in R0 resection rates, have increased interest in neo-adjuvant treatment strategies. Here we review biomarkers for early diagnosis of PDAC and patient selection for a neo-adjuvant approach. We also review the current evidence for different chemotherapy regimens in this setting, as well as the role of chemoradiotherapy and immunotherapy, and we discuss ongoing trials.

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“…For diagnosis of pancreatic cancer, no such FDA approved lncRNA-based diagnosis has been reported so far. However, researches on the development of ncRNA testing as diagnosis or supplementary diagnostic tools for pancreatic cancer have received much attention and revealed some novel markers for pancreatic cancer [149][150][151][152].…”

Section: The Role Of Non-coding Rnas In the Diagnosis Of Pancreatic Cancermentioning

confidence: 99%

Non-Coding RNAs in Pancreatic Cancer Diagnostics and Therapy: Focus on lncRNAs, circRNAs, and piRNAs

Hallak

Philip

et al. 2021

Cancers

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Pancreatic cancer is an aggressive malignance with high mortality. The lack of early diagnosis and effective therapy contributes to the high mortality of this deadly disease. For a long time being, the alterations in coding RNAs have been considered as major targets for diagnosis and treatment of pancreatic cancer. However, with the advances in high-throughput next generation of sequencing more alterations in non-coding RNAs (ncRNAs) have been discovered in different cancers. Further mechanistic studies have demonstrated that ncRNAs such as long noncoding RNAs (lncRNA), circular RNAs (circRNA) and piwi-interacting RNA (piRNA) play vital roles in the regulation of tumorigenesis, tumor progression and prognosis. In recent years, increasing studies have focused on the roles of ncRNAs in the development and progression of pancreatic cancer. Novel findings have demonstrated that lncRNA, circRNA, and piRNA are critically involved in the regulation of gene expression and cellular signal transduction in pancreatic cancer. In this review, we summarize the current knowledge of roles of lncRNA, circRNA, and piRNA in the diagnosis and prognosis of pancreatic cancer, and molecular mechanisms underlying the regulation of these ncRNAs and related signaling in pancreatic cancer therapy. The information provided here will help to find new strategies for better treatment of pancreatic cancer.

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Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy

Cited by 25 publications

References 291 publications

circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway

circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway

Neoadjuvant Treatment for Pancreatic Adenocarcinoma: A False Promise or an Opportunity to Improve Outcome?

Non-Coding RNAs in Pancreatic Cancer Diagnostics and Therapy: Focus on lncRNAs, circRNAs, and piRNAs

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