Exosomal long non-coding RNAs in gastrointestinal cancer: chemoresistance mediators and therapeutic targets

Abstract

Gastrointestinal (GI) cancer is a series of malignant cancer mainly affecting the GI tract. Chemotherapy is one of the most treatment strategies used in GI cancer treatment, especially in advanced cases. However, the challenge of chemoresistance significantly compromises treatment success, resulting in poorer clinical outcomes and increased metastatic potential. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and are implicated in various disease processes. Recent research has demonstrated that lncRNAs can be packaged within exosomes, thereby facilitating intercellular communication and potentially transferring chemoresistance traits among cancer cells. This review focuses on the biogenesis and functional roles of exosomal lncRNAs in promoting chemoresistance across different GI cancers. We highlight specific lncRNAs, elucidate their mechanisms of action, and discuss innovative therapeutic strategies aimed at targeting these molecules in gastrointestinal malignancies. By exploring these intricate interactions, we aim to identify novel approaches to overcome chemoresistance and improve the efficacy of treatments for GI cancer.

Keywords: Chemoresistance; Exosomal lncRNAs; Gastrointestinal cancers; Intercellular communication; Therapeutic targets.

Fig. 1

Mechanisms of Exosome-Mediated lncRNA Transfer between Secreting and Recipient Cells. This figure illustrates the detailed mechanisms by which long non-coding RNAs (lncRNAs) are packaged, secreted, and transferred between cells via exosomes. Exosomes, small extracellular vesicles (30–100 nm), originate from intraluminal vesicles (ILVs) within multivesicular endosomes (MVEs) in the secreting cell. The ESCRT complex facilitates the formation of MVEs, which either fuse with lysosomes for degradation or with the plasma membrane to release exosomes. Once exosomes enter the extracellular space, they can be taken up by recipient cells through various processes, including phagocytosis, micropinocytosis, endocytosis, or direct fusion with the cell membrane. Upon entry into the recipient cell, exosomes are either directed towards lysosomal degradation or processed through the endosomal pathway. The lncRNAs carried within these exosomes can then be released and act on the recipient cell's gene regulatory machinery, affecting mRNA translation and protein production, and modulating diverse cellular functions. This mechanism highlights the significance of exosome-mediated lncRNA transfer in intercellular communication and gene regulation. Created in BioRender

Fig. 2

Mechanistic roles of lncRNAs in GI cancers. This figure illustrates the involvement of various long non-coding RNAs (lncRNAs) in the regulation of critical signaling pathways across different GI cancers, including colorectal, gastric, esophageal, hepatocellular, and pancreatic cancers. In colorectal cancer, lncRNAs such as SNHG11, CACClnc, CCAL, H19, and FAL1 modulate pathways related to efflux pump regulation (ABCC1), DNA repair (RAD51), apoptosis (β-catenin, Beclin), and drug resistance (Bevacizumab). Similarly, in gastric cancer, lncRNAs DACT3-AS1 and FGD5-AS1 promote cancer cell proliferation via SIRT1 and Cyclin D1/E pathways, with implications for resistance to drugs like Oxaliplatin and Cisplatin. Esophageal cancer features lncRNAs such as MIAT and POU3F3, which influence metabolic dysregulation, EMT (epithelial-mesenchymal transition), and cell survival through interactions with key proteins like TAF1, SREBF1, and Interleukin-6. Hepatocellular and pancreatic cancers demonstrate the regulation of EMT and apoptosis by lncRNAs LncROR and associated pathways (TGFβ, Hippo/YAP), which also influence response to chemotherapeutic agents like Camptothecin and Gemcitabine. Created in BioRender

Fig. 3

Key Mechanisms of lncRNA-Mediated Chemoresistance in Cancer. This figure highlights mechanisms by which long non-coding RNAs (lncRNAs) drive chemoresistance in cancer. First, enhanced DNA repair by lncRNAs such as CACC1nc and SBF2-AS1 increases resistance to drugs like Oxaliplatin and Temozolomide in colorectal cancer and glioblastoma. Second, reduced apoptosis and ferroptosis, facilitated by lncRNAs such as DACT3-AS1 and AGAP2-AS1, protects gastric and breast cancer cells from chemotherapy-induced cell death. Third, epigenetic modification and chromatin remodeling, mediated by lncRNAs like HOTTIP and HOTAIR, fosters resistance to Cisplatin and Temozolomide in gastric cancer and glioblastoma. Fourth, alternative signaling pathways, modulated by lncRNAs MIAT and H19, contribute to resistance in esophageal and breast cancers against Paclitaxel and Doxorubicin. Finally, tumor microenvironment modulation involving lncRNAs like POU3F3 and CCAL from cancer-associated fibroblasts, and H19 from TAMs. They are indicated to enhance resistance to Cisplatin, Oxaliplatin, and Temozolomide in esophageal, colorectal cancer, and glioblastoma, respectively. Created in BioRender

Fig. 4

Comprehensive overview of exosomal lncRNAs and their mechanistic roles in mediating chemoresistance across gastrointestinal cancers. The left panel depicts the biogenesis and secretion of exosomal lncRNAs via the endosomal sorting pathway, including multivesicular body formation and exosome release. The middle panel details specific lncRNAs associated with resistance to various chemotherapeutic agents, including oxaliplatin (OXA), cisplatin (DDP), paclitaxel (PTX), bevacizumab (BEV), camptothecin (CPT), gemcitabine (GEM), and propofol, highlighting their involvement in key regulatory pathways such as PI3K/AKT, β-catenin signaling, and SIRT1 modulation. These lncRNAs influence critical cellular processes, including drug efflux, DNA repair, apoptosis suppression, cellular proliferation, tumor microenvironment remodeling, and epithelial-to-mesenchymal transition (EMT). The right panel summarizes the downstream functional consequences of these pathways, emphasizing their contributions to therapeutic resistance and tumor progression. Created in Biorender