Lung Cancer Chemoresistance: Insights into the Regulatory Role of lncRNAs

From epigenetics to metastasis: Multifaceted roles of lncRNAs in gastric cancer

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, largely due to its high metastatic potential and poor prognosis at advanced stages. Epithelial–mesenchymal transition (EMT) is a pivotal biological process that facilitates tumor invasion, dissemination, and therapeutic resistance in GC. In recent years, long non-coding RNAs (lncRNAs) have emerged as critical regulators of gene expression, orchestrating multiple aspects of cancer progression through epigenetic, transcriptional, and post-transcriptional mechanisms. This review provides a comprehensive overview of the current understanding of lncRNA-mediated regulation of EMT and metastasis in gastric cancer. We summarize how lncRNAs function as epigenetic modulators, competing endogenous RNAs (ceRNAs), and molecular scaffolds to regulate EMT-associated transcription factors, signaling pathways, and chromatin dynamics. In particular, key oncogenic pathways such as Wnt/β-catenin, PI3K/AKT, STAT3, and NF-κB are highlighted as major downstream targets of lncRNA activity. Furthermore, we discuss the involvement of lncRNAs in tumor microenvironment remodeling, hypoxia response, angiogenesis, immune regulation, and extracellular matrix reorganization, all of which contribute to metastatic progression. Importantly, dysregulated lncRNA expression is closely associated with clinicopathological features and patient outcomes, underscoring their potential as diagnostic and prognostic biomarkers. In addition, the therapeutic targeting of lncRNAs represents a promising strategy for overcoming metastasis and treatment resistance in gastric cancer. Overall, this review integrates recent advances in the field and provides insights into the complex regulatory networks governed by lncRNAs, highlighting their translational potential in improving GC management.

Circular RNAs in NSCLC: Their Role in Tumorigenesis, Tumor Microenvironment Reshaping, and Response to Therapies

Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms involved in its development and response to therapies remain poorly understood. Previous studies have unraveled the pro- or anti-tumoral roles of circular RNAs (circRNAs) in numerous cancers. These mostly non-coding RNAs consist of a single-strand RNA forming a stable closed loop. CircRNA expression is often dysregulated in cancers, including lung cancer. An increasing number of studies have been published describing the role of circRNAs in lung tumor progression and/or resistance to therapies. Most of these studies have focused on how circRNAs impact cancer cells in a cell-autonomous manner, but less is known about the role of tumoral circRNAs in the crosstalk between cancer cells and cells from the tumor microenvironment (TME). In this review, focusing on non-small cell lung cancer (NSCLC), we provide a comprehensive and up-to-date analysis of the current knowledge in this emerging field. We highlight key molecular mechanisms by which tumor-derived circRNAs reshape the NSCLC tumor immune microenvironment. We also discuss recent findings showing their contributions to most NSCLC hallmarks, including those newly described in 2022, as well as their involvement in NSCLC’s escape from therapies. All these studies clearly open avenues for translational applications of circRNAs in NSCLC, as either potential biomarkers or therapeutic targets, although current limitations clearly need to be overcome to translate circRNAs into the clinic.

The regulatory role of non-coding RNAs in taxane resistance of breast cancer.

Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context‑dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane‑sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.

The lncRNA SOX2OT Drives Non-Small Cell Lung Cancer Progression and Metastasis by Suppressing miR-143

In terms of cancer-related death, non-small cell lung cancer (NSCLC), the world’s leading cause, highlights the need for continued research into the genetic factors that influence tumor growth. Long non-coding RNAs (lncRNAs) are now well recognized as essential regulators of oncogenic signaling cascades; nevertheless, the specific role and molecular basis of the SOX2 overlapping transcript (SOX2OT) in NSCLC are not entirely understood. This study examined the functional importance of SOX2OT and its regulatory interactions with tumor-suppressive microRNAs in NSCLC cells. In A549 and Calu-3 cells, RNA interference-mediated SOX2OT silencing dramatically reduced cellular proliferation, migration, and invasiveness. Moreover, SOX2OT knockdown was associated with inhibition of epithelial–mesenchymal transition (EMT), alongside induction of cell cycle arrest and activation of apoptotic pathways. Integrated transcriptomic profiling and bioinformatic prediction analyses identified miR-143 as a putative downstream effector of SOX2OT activity. Consistently, depletion of SOX2OT resulted in marked elevation of miR-143 expression, which corresponded with downregulation of oncogenic mediators, including STAT3, EZH2, and CXCL13. As a result of SOX2OT suppression, both the transcript and the protein levels of PTEN were restored. Further functional characterization demonstrated that SOX2OT knockdown inhibits EMT progression by decreasing mesenchymal markers and EMT-related transcription factors (TFs) while concomitantly enhancing epithelial marker expression. Collectively, these findings suggest that SOX2OT contributes to NSCLC pathogenesis through regulation of a miR-143-centered signaling network that influences oncogenic signaling, cellular survival, and metastatic potential. Targeting the SOX2OT/miR-143 regulatory axis may therefore represent a promising therapeutic approach for NSCLC, while also underscoring the broader importance of lncRNA-mediated post-transcriptional regulation in lung cancer biology.

Long non-coding RNAs as master regulators of cancer metastasis and therapeutic resistance.

Metastasis and therapeutic resistance remain the principal causes of cancer-related mortality, reflecting the failure of current therapies to eradicate disseminated and treatment-refractory tumor cells. Long non-coding RNAs, once considered transcriptional noise, have now emerged as pivotal regulators of cancer progression, acting through diverse mechanisms to modulate signaling pathways, transcriptional programs, tumor metabolism, and the tumor microenvironment. Accumulating evidence demonstrates that lncRNAs orchestrate epithelial-mesenchymal transition, metabolic reprogramming, and immune evasion, thereby enabling metastatic dissemination and fostering resistance to chemotherapy. Moreover, recent discoveries have revealed that certain lncRNAs can encode functional micropeptides, further expanding their biological and therapeutic relevance. In this review, we systematically summarize current advances in lncRNA-mediated regulation of cancer metastasis and drug resistance, with particular emphasis on their roles in oncogenic signaling cascades, transcriptional control, immune cell reprogramming, and metabolic remodeling. we also discuss emerging therapeutic strategies targeting lncRNAs, including antisense oligonucleotides, CRISPR-based approaches, and lncRNA-encoded micropeptides interventions. Finally, we highlight key challenges, including context-dependent lncRNA functions, tumor heterogeneity, delivery, off-target effects, and biomarker standardization, and discuss multi-omics, single-cell, and spatial approaches may facilitate the translation of lncRNA biology into precision oncology.

Long non-coding RNAs in colorectal cancer: shaping the tumour microenvironment and advancing precision oncology.