LncRNAs in Cancer: Shaping Tumor Progression & Paving New Paths for Treatment

Abstract

Long non-coding RNAs, or lncRNAs, are relatively new participants in the game of cancer biology, fitting into no less than this already erased notion of "junk" DNA, which has been rewritten to accommodate critical roles in gene expression, tumor progression, immune evasion, and metastasis, which are cellular processes. This article takes a closer look at the complex roles of lncRNAs in cancer by examining their roles as oncogenes and tumor suppressors, affecting the tumor microenvironment, and supporting the survival of cancer stem cells. In addition, opportunities to use lncRNAs as therapeutic targets and diagnostic biomarkers have been identified, and such emerging strategies as RNAi, ASOs, and CRISPR/Cas9 open new avenues for therapy. Although challenges still exist regarding the complete elucidation and targeting of lncRNAs, current studies are paving the road for newer cancer therapies. This review highlights a great hope for the treatment and diagnostics of cancers by lncRNAs, a new era in oncology.

Introduction

Cancer has been viewed as a complex disease concerning genomic mutations and epigenetic alterations, as well as complex molecular networks. But one of the most interesting findings from researchers in recent years is that the so-called "junk" DNA previously called long noncoding RNAs (lncRNAs) was a significant determinant of gene expression, cellular differentiation, and tumor development. These RNA molecules, typically more than 200 nucleotides in length, do not code for proteins but exhibit profound regulatory roles in normal cellular phenomena as well as in pathological states such as cancer. Indeed, scientists are continually uncovering the various roles of lncRNAs in cancer biology, and these molecules now appear to be promising biomarkers for diagnosis and prognosis and are attractive targets for new cancer therapies.

Here, the complex functions of lncRNAs involved in cancer progression and their potential as therapeutic targets are reviewed, along with the implications for future treatments in oncology.

The Complex Role of lncRNAs in Cancer

Long non-coding RNAs have emerged as important factors in cancer research due to their effects on gene expression, partly through mechanisms of chromatin remodeling, transcriptional regulation, and post-transcriptional control. What's remarkable is that lncRNAs very often display tissue- or cell-specific expression, which is particularly relevant in the context of cancer settings where their deregulation often serves to initiate the process of tumor formation, progression, and metastasis.

lncRNAs as Oncogenes and Tumor Suppressors

LncRNAs may act as oncogenes or as tumor suppressors depending on the context in which they are found. For example, one of the most well-known and widely studied lncRNAs is HOTAIR (HOX transcript antisense RNA), which is demonstrated to have a function in promoting tumor invasion and metastasis in breast cancer through changes in chromatin states and reduced expressions of tumor suppressor genes. MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) is another lncRNA whose function is to be associated with metastasis in cancers such as lung, liver, and colorectal cancers.

On the other hand, some lncRNAs act as tumor suppressors. For instance, MEG3 (Maternally Expressed Gene 3) was reported to inhibit proliferation and induce apoptosis in glioma and hepatocellular carcinoma. In summary, lncRNAs have diametric functions in tumorigenesis.

lncRNAs and the Tumor Microenvironment

In addition to that, lncRNAs are intricately involved in the modulation of the tumor microenvironment, which has a pivotal role in cancer progression. Tumor cells communicate with surrounding cells, such as immune cells, stromal cells, and endothelial cells through signaling pathways that are generally mediated by lncRNAs. For example, lncRNA PVT1 Plasmacytoma Variant Translocation 1 facilitates angiogenesis and supports a hypoxic environment within the tumor, to support the survival of cancer cells and prevent them from being therapy-responsive.

They may also influence cancer immune evasion by targeting immune checkpoints and reprogramming functions of immune cells. Hence, this interaction between lncRNAs and the TME can be a gateway for intervening in the immune response to treat cancer.

lncRNAs in Cancer Stem Cells

These cells form a minimal percentage of cells in a tumor with self-renewal and differentiation capabilities. These factors contribute to tumor growth and impart resistance to conventional therapies. LncRNAs are involved in CSC's maintenance and survival for stemness. Thus, lncRNA H19 contributes to stem-like properties in cancer cells from both colorectal and breast cancers, thus enhancing its tumorigenicity and chemoresistance.

Researchers are, thus, finding new therapeutic strategies that target CSC-associated lncRNAs to eliminate the root cause of cancer recurrence and metastasis.

Therapeutic Potential of Targeting lncRNAs in Cancer

Given the regulatory functions of lncRNAs in cancer biology, they have emerged as promising therapeutic targets. Several approaches are currently being explored to target lncRNAs, including RNA interference (RNAi), antisense oligonucleotides (ASOs), and CRISPR/Cas9-based gene editing technologies.

RNA Interference (RNAi)

RNAi constitutes a physiological cellular process that can be used to selectively suppress specific lncRNAs. It can therefore be adapted for the treatment of cancer by specifically inhibiting oncogenic lncRNA expression, thus interrupting their tumorigenic functions. Indeed, in a variety of preclinical models, inhibition of lncRNAs like HOTAIR and MALAT1 resulted in decreased tumor growth and metastasis in animal models.

Antisense Oligonucleotides (ASOs)

ASOs are short, synthetic strands of nucleic acids designed to bind to complementary lncRNA sequences, thereby inhibiting their function. ASOs have shown promise in clinical trials for various diseases, including cancer. For instance, targeting MALAT1 with ASOs has been shown to reduce metastasis in lung cancer models, highlighting the therapeutic potential of this approach.

CRISPR/Cas9 Gene Editing

The CRISPR/Cas9 system, widely known for its gene-editing capabilities, can also be used to specifically knock out lncRNAs involved in cancer progression. By directly disrupting the genomic loci encoding oncogenic lncRNAs, CRISPR/Cas9 offers a powerful tool to investigate and potentially reverse the oncogenic effects of these molecules.

While these therapeutic strategies are still in the early stages of development, their potential to selectively target lncRNAs involved in cancer progression represents a new frontier in oncology.

lncRNAs as Biomarkers for Cancer Diagnosis and Prognosis

LncRNAs are not only potential therapeutic targets but also valuable biomarkers for cancer diagnosis and prognosis. Due to their tissue-specific expression and stability in body fluids such as blood and urine, lncRNAs can serve as non-invasive biomarkers for early cancer detection and monitoring.

For instance, lncRNA PCA3 is a well-established biomarker for prostate cancer, and its expression level in urine has been used to improve the accuracy of prostate cancer diagnosis, reducing the need for invasive biopsies. Similarly, circulating levels of lncRNA HULC (Highly Upregulated in Liver Cancer) have been proposed as a biomarker for hepatocellular carcinoma, offering a potential tool for early detection and prognosis.

The use of lncRNAs as biomarkers is particularly promising in cancers that are difficult to diagnose at an early stage, such as pancreatic and ovarian cancers. By incorporating lncRNA profiling into routine cancer screening, clinicians may improve the accuracy of diagnoses and tailor treatments to individual patients' molecular profiles.

Challenges and Future Directions

Although lncRNAs in cancer have seen significant progress in their study, many challenges have to be cleared. First, the functional characterization of lncRNAs is complicated due to their multivalent mechanism of action, and most lncRNAs remain poorly understood. Finally, therapeutic approaches targeting lncRNAs must overcome the delivery-related problems of RNA-based treatments to tumor tissues without any off-target effects.

In addition, lncRNAs often function in concert with other regulatory molecules such as microRNAs and transcription factors, so the broader network of interactions in which a particular lncRNA is involved needs to be considered.

Despite these challenges, research is progressively illuminating the functional roles of lncRNAs in cancer and opening new avenues for diagnostic and therapeutic applications. As more lncRNAs are identified and their roles in cancer are understood, bringing lncRNA-targeted therapies into clinical practice will be transformative in cancer treatment.

Conclusion

Long non-coding RNAs are growing in importance as key regulators of tumor progression, influencing nearly every area of cancer biology from gene expression and immune evasion to metastasis and drug resistance. As the knowledge about lncRNAs grows, so does the potential for them as therapeutic targets and diagnostic biomarkers. Hence the progress of lncRNA-targeted therapies, together with innovations in RNA delivery technologies and gene editing, promises future therapies of higher efficacy and specificity in cancer. Those molecules hitherto underrated can shape the future of oncology and further promise hope for cancer patients.

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