Dynamic feedback between IL-6 and TWIST1 drives pancreatic cancer progression
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Background Interleukin-6 (IL-6) and twist family bHLH transcription factor 1 (TWIST1) are critical regulators of cancer progression, including in pancreatic ductal adenocarcinoma (PDAC), but how they dynamically interact remains unclear. Therefore, this study aimed to elucidate the interaction between IL-6 and TWIST1 and explore the underlying mechanisms involved in PDAC progression. Methods The expression levels of IL-6, IL-6R, and TWIST1 were examined in 66 PDAC patient specimens, and their correlations with clinicopathological parameters and overall survival were analyzed. Integrative bioinformatics and experimental validation identified miR-543 as a key upstream regulator of TWIST1. The IL-6/miR-543/TWIST1 feedback circuit was subsequently verified in PDAC cell lines using quantitative PCR, western blotting, and luciferase reporter assays. Chromatin immunoprecipitation and luciferase reporter assays further confirmed the binding of TWIST1 to the IL-6 promoter.xenograft models were further established to investigate both the functional relevance and therapeutic blockade of this signaling loop. Results Elevated expression of IL-6, IL-6R, and TWIST1 was detected in PDAC tissues and was significantly associated with poor patient prognosis. Bioinformatic and experimental analyses identified miR-543 as a pivotal mediator linking IL-6 signaling to TWIST1 regulation.andexperiments demonstrated that IL-6 modulated TWIST1 expression through miR-543, thereby promoting PDAC cell migr
Abstract
Background Interleukin-6 (IL-6) and twist family bHLH transcription factor 1 (TWIST1) are critical regulators of cancer progression, including in pancreatic ductal adenocarcinoma (PDAC), but how they dynamically interact remains unclear. Therefore, this study aimed to elucidate the interaction between IL-6 and TWIST1 and explore the underlying mechanisms involved in PDAC progression. Methods The expression levels of IL-6, IL-6R, and TWIST1 were examined in 66 PDAC patient specimens, and their correlations with clinicopathological parameters and overall survival were analyzed. Integrative bioinformatics and experimental validation identified miR-543 as a key upstream regulator of TWIST1. The IL-6/miR-543/TWIST1 feedback circuit was subsequently verified in PDAC cell lines using quantitative PCR, western blotting, and luciferase reporter assays. Chromatin immunoprecipitation and luciferase reporter assays further confirmed the binding of TWIST1 to the IL-6 promoter.xenograft models were further established to investigate both the functional relevance and therapeutic blockade of this signaling loop. Results Elevated expression of IL-6, IL-6R, and TWIST1 was detected in PDAC tissues and was significantly associated with poor patient prognosis. Bioinformatic and experimental analyses identified miR-543 as a pivotal mediator linking IL-6 signaling to TWIST1 regulation.andexperiments demonstrated that IL-6 modulated TWIST1 expression through miR-543, thereby promoting PDAC cell migration, invasion, proliferation, and clonogenic growth. TWIST1, in turn, transcriptionally upregulated IL-6 expression, forming a self-reinforcing feedback circuit. Pharmacological blockade of this loop with Tocilizumab effectively attenuated PDAC progression. Conclusions The IL-6/miR-543/TWIST1 axis supports a dynamic feedback circuit that is associated with PDAC malignancy. Therapeutic targeting of this loop may provide an effective strategy to impede disease progression.