Dysregulated miRNAs modulate tumor microenvironment associated signaling networks in pancreatic ductal adenocarcinoma

Abstract

The desmoplastic and complex tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) has presented tremendous challenges for developing effective therapeutic strategies. Strategies targeting tumor stroma, albeit with great potential, have met with limited success due to the lack of knowledge on the molecular dynamics within the tumor microenvironment (TME). In pursuit of a better understanding of the influence of miRNAs on TME reprogramming and to explore circulating miRNAs as diagnostic and prognostic biomarkers for PDAC, using RNA-seq, miRNA-seq, and single-cell RNA-seq (scRNA-seq), we investigated the dysregulated signaling pathways in PDAC TME modulated by miRNAs from plasma and tumor tissue. Our bulk RNA-seq in PDAC tumor tissue identified 1 445 significantly differentially expressed genes with extracellular matrix and structure organization as the top enriched pathways. Our miRNA-seq identified 322 and 49 abnormally expressed miRNAs in PDAC patient plasma and tumor tissue, respectively. We found many of the TME signaling pathways were targeted by those dysregulated miRNAs in PDAC plasma. Combined with scRNA-seq from patient PDAC tumor, our results revealed that these dysregulated miRNAs were closely associated with extracellular matrix (ECM) remodeling, cell-ECM communication, epithelial-mesenchymal transition, as well as immunosuppression orchestrated by different cellular components of TME. The findings of this study could assist the development of miRNA based stromal targeting biomarkers or therapy for PDAC patients.

miRNA signatures underlie chemoresistance in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line MIA PaCa-2 GR

“…miRNA-seq libraries were constructed using the QIAseq miRNA library kit (QIAGEN, Germantown, MD) following the manufacturer’s instructions. miRNAs were processed as previously recorded ( Liu et al, 2023 ). Briefly, 3′ and 5′ adapters, along with unique molecular identifiers, were added to small RNAs.…”

“…miRNA data were processed as previously recorded ( Liu et al, 2023 ). All sequencing data were demultiplexed and converted to fastq files using bcl2fastq (Illumina Inc., San Diego, CA).…”

“…Library size and quality were examined using the TapeStation 2200 (Agilent, Santa Clara, CA). miRNA-seq libraries were sequenced at 76-bp single-end on an Illumina NextSeq 550 at the Center for Genomics, LLU, with a final loading concentration of 2.1 p.m. Frontiers in Genetics frontiersin.org miRNA identification and differential miRNA expression analysis miRNA data were processed as previously recorded (Liu et al, 2023). All sequencing data were demultiplexed and converted to fastq files using bcl2fastq (Illumina Inc., San Diego, CA).…”

Research Progress on Quercetin's Biological Activity and Structural Modification Based on Its Antitumor Effects

“…[34] miRNAs are small single-stranded noncoding RNA molecules related to biological behaviors such as proliferation, apoptosis, negative regulation of gene expression, and the etiology of malignant tumors. [36] Quercetin decreases the activity of oral squamous cell carcinoma, increases the apoptosis rate, upregulates the expression of miR-22, and inhibits the expression of Wnt1 and β-catenin; Wnt1 is the target signal of miR-22. Knocking out miR-22 or using inhibitors can weaken the inhibitory and apoptotic effects of quercetin in oral squamous cell carcinoma, indicating that quercetin can inhibit the growth of oral squamous cell carcinoma by inducing the expression of miR-22 and inhibiting the Wnt1/β-catenin pathway.…”

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“…miRNA-seq libraries were constructed using the QIAseq miRNA library kit (QIAGEN, Germantown, MD) following the manufacturer's instructions. miRNAs were processed as previously recorded (Liu et al, 2023). Briefly, 3′ and 5′ adapters, along with unique molecular identifiers, were added to small RNAs.…”