NNT-AS1 inCAFs-derived exosomes promotes progression and glucose metabolism through miR-889-3p/HIF-1α in pancreatic adenocarcinoma

Sep 21, 2026

Pancreatic adenocarcinoma exhibits poor survival and aggressive behavior driven by metabolic reprogramming and tumor microenvironment signaling. This work investigates how cancer-associated fibroblasts (CAFs) communicate with tumor cells via CAF-derived exosomes, focusing on the lncRNA NNT-AS1. Exosomal NNT-AS1 is shown to modulate glucose metabolism, proliferation, and metastasis in PDAC cells. Mechanistically, NNT-AS1 functions as a molecular sponge for miR-889-3p, thereby regulating HIF-1α and glycolytic remodeling, identifying potential therapeutic targets for PDAC.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Background

Tumor metabolic reprogramming and HIF signaling

Role of CAFs and tumor microenvironment

Exosomes and long noncoding RNAs

Study rationale and prior findings

NNT-AS1 and cancer progression

miR-889-3p and signaling context

Methods overview

Exosome isolation and identification

Gene expression analysis and interaction validation

Mechanistic framework

NNT-AS1/miR-889-3p/HIF-1α axis

Effects on glycolysis, proliferation, and metastasis

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN NNT‑AS1 inCAFs‑derived exosomes promotes progression and glucose metabolism through miR‑889‑3p/HIF‑1α in pancreatic adenocarcinoma Pingping Zhang1, Qun Wang2, Weijun Lu2, Feng Zhang2, Dongde Wu2 & Junwei Sun2* It is metabolic and signaling crosstalk between stromal cells and tumors in the tumor microenvironment, which influences several aspects of tumor formation and drug resistance, including metabolic reprogramming. Despite considerable findings linking lncRNAs in HIF‑1‑related regulatory networks to cancer cell, little emphasis has been given to the role in communication between cancer‑associated fibroblasts (CAFs) and tumor cells. Previously, we observed that NNT‑AS1 was substantially expressed in CAFs cells and CAFs exosomes, and subsequently investigated the influence of CAFs exosomal NNT‑AS1 on glucose metabolism, proliferation, and metastasis of pancreatic ductaladenocarcinoma (PDAC) cells. Transmission electron microscopy was used to examine exosomes secreted by PDAC patient‑derived CAFs. qRT‑PCR was used to evaluate the expression of NNT‑AS1, miR‑889‑3p, and HIF‑1. The role of CAFs‑derived exosomal NNT‑AS1 in PDAC cell progression and metabolism have been identified. Dual luciferase reporter assays examined the binding between NNT‑AS1, miR‑889‑3p, and HIF‑1. After PDAC cells co‑culture exosomes secreted by CAFs, we found that they alter glucose metabolism, proliferation, and metastasis. In PDAC cells, CAF‑derived exosomal lncRNA NNT‑AS1 acted as a molecular sponge for miR‑889‑3p. Furthermore, HIF‑1 could be targeted by miR‑889‑3p and was controlled by NNT‑AS1. This study explores the mechanism by which NNT‑AS1 influences the interaction of CAFs on glycolytic remodeling, proliferation, and metastasis of tumor cells through regulating miR‑889‑3p/HIF‑1α, which also helps discover new clinical treatment targets for PDAC. Keywords CAFs-derived exosomes, NNT-AS1, PDAC, miR-889-3p, HIF-1α, Glucose metabolism Abbreviations NNT-AS1 PDAC CAFs NF FAP TMELncRNACCK-8 HIF-1 LDHA PKM2 SDH FH Nicotinamide nucleotide transhydrogenase-antisense RNA1 Pancreatic ductal adenocarcinoma Cancer-associated fibroblasts Normal fibroblasts Fibroblast activating protein Tumor microenvironment Long noncoding RNA Cell counting kit-8 Hypoxia inducible factor 1 Lactate dehydrogenase AM2-type pyruvate kinase Succinate dehydrogenase Fumarate hydratase 1Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2Department of Hepatic & Biliary & Pancreatic Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. *email: [junweisunHBCH@hotmail.com](junweisunHBCH@hotmail.com) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) OD Optical density SD Standard deviation Pancreatic ductal adenocarcinoma is one of the most aggressive gastrointestinal malignancies, with a 5-year survival rate of less than 10%1. Metabolic reprogramming, often known as the Warburg effect, is one of cancer’sten hallmarks. It is important for cancer growth, including invasion and metastasis. Changes in the microenvironment can activate and maintain HIF, which, in turn, stimulates the transcription of related genes involved in metabolic reprogramming and PDAC generation, invasion, metastasis, and angiogenesis2,3. Meanwhile, cancerassociated fibroblasts (CAFs), a kind of activated fibroblast, are present in practically all solid tumors, especially in pancreatic, breast, and prostate cancers4–6. CAFs play a critical role in the formation and progression of a variety of cancers since they are one of the most important components of the tumor microenvironment (TME) . Tumor cells and CAFs communicate in a variety of ways. It has been found that CAFs can aid cancer cells in acquiring energy, synthetic pro

FAQs

What biological pathway does the study focus on in PDAC?

The study focuses on an exosomal axis involving lncRNA NNT-AS1, miR-889-3p, and HIF-1α, linking CAF-derived signaling to glycolytic remodeling in PDAC cells.

How are CAF-derived exosomes assessed in the experiments?

Transmission electron microscopy is used to examine exosomes secreted by patient-derived CAFs, followed by molecular assays such as qRT-PCR and binding validation with dual luciferase reporter assays.

What effects do CAF-derived exosomal NNT-AS1 have on PDAC cells?

CAF-derived exosomal NNT-AS1 alters glucose metabolism, promotes proliferation, and increases metastasis in PDAC cells after co-culture.

Sep 21, 2026

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