Long non-coding RNAs (lncRNAs) are molecules within our cells that do not carry instructions for making proteins, unlike messenger RNAs. These RNA molecules, typically over 200 nucleotides in length, perform diverse functions related to regulating gene activity and maintaining cellular organization. One well-studied lncRNA is Metastasis Associated Lung Adenocarcinoma Transcript 1, commonly known as MALAT1. It gained recognition due to its discovery in lung cancer research, where its expression was elevated in tumors with a higher likelihood of spreading. Understanding MALAT1’s roles provides insight into normal cellular processes and disease development.
The Cellular Functions of MALAT1
In a healthy cell, MALAT1 carries out several functions, primarily within the nucleus. It is abundantly expressed across various tissues and influences gene activity. This molecule participates in gene regulation at both the transcriptional and post-transcriptional levels, meaning it can influence genes as they are being copied from DNA and after the initial RNA copy is made.
MALAT1 also contributes to alternative splicing, a process that allows a single gene to produce multiple different protein versions. It influences alternative splicing by modulating the phosphorylation of SR splicing factors. These factors are proteins that guide the cellular machinery responsible for cutting and rejoining RNA segments, producing diverse protein forms from a single genetic blueprint. MALAT1 associates with these SR proteins within specific nuclear domains.
MALAT1 is predominantly located within the cell’s nucleus, specifically in structures called nuclear speckles. These nuclear speckles are rich in components involved in pre-mRNA processing and transcription factors, acting as organizational hubs. MALAT1 is found at the periphery of these speckles, contributing to the organization of cellular machinery involved in gene expression and RNA processing.
The Link Between MALAT1 and Cancer
In many types of cancer, MALAT1’s normal functions become altered or dysregulated. Numerous cancers exhibit high levels of MALAT1, often associated with tumor progression. This elevated expression contributes to several hallmarks of cancer, including uncontrolled cell multiplication and evasion of natural cell death processes. MALAT1 can interact with various oncogenes and tumor suppressors, influencing signaling pathways that drive cancer development.
MALAT1 promotes the growth and survival of cancer cells. Its overexpression has been linked to increased proliferation and tumor formation in various solid tumors. For example, in breast cancer, elevated MALAT1 levels correlate with lymph node metastasis and reduced disease-free survival. In colorectal cancer, higher MALAT1 expression is associated with a greater risk of metastasis and poorer overall survival.
MALAT1’s involvement in cancer includes its contribution to metastasis, the spread of cancer cells from the primary tumor to distant sites. It influences cell migration and invasion, which are necessary steps for cancer cells to break away and establish new tumors. MALAT1 can regulate a “metastatic signature” of genes.
Due to its consistent overexpression in many tumor types and its association with disease progression, MALAT1 also holds potential as a prognostic biomarker to predict disease outcome or aggressiveness. For instance, in bladder cancer, high MALAT1 expression correlates with advanced tumor stage and poorer overall survival.
Involvement in Non-Cancerous Conditions
Beyond its connection to cancer, MALAT1’s influence extends to various non-cancerous conditions. Its expression is often elevated in conditions related to diabetes, such as diabetic retinopathy, which affects blood vessels in the eyes, and diabetic nephropathy, affecting the kidneys. In these diabetic complications, MALAT1 contributes to pro-inflammatory responses and programmed cell death in different cell types.
MALAT1’s role in diabetic retinopathy, a leading cause of blindness, involves its impact on inflammation and angiogenesis, the formation of new blood vessels. It can influence the expression of inflammatory transcripts and regulate the antioxidant defense system in retinal cells. In diabetic nephropathy, MALAT1 upregulation has been observed in kidney tissues and can contribute to cell damage, apoptosis, and inflammatory responses.
MALAT1 is also connected to cardiovascular disease, influencing processes like inflammation and cell death in heart and blood vessel tissues. Elevated MALAT1 levels can trigger inflammatory cytokines like TNF-α, IL-1β, and IL-6, which contribute to inflammation and cardiomyopathy. It has also been implicated in inflammatory and autoimmune responses more broadly, participating in regulating the body’s immune system and impacting various chronic inflammatory conditions.
Targeting MALAT1 for Future Therapies
The widespread involvement of MALAT1 in various diseases, particularly cancer and diabetic complications, makes it an appealing target for new therapeutic strategies. The primary approach for targeting MALAT1 involves using molecules designed to reduce its levels or block its function within diseased cells. Disrupting MALAT1’s activity aims to reverse its disease-promoting effects.
Antisense oligonucleotides (ASOs) are a key technology being explored to target RNAs like MALAT1. These are short, synthetic single-stranded molecules that act as “molecular silencers.” When an ASO binds to its complementary RNA target, such as MALAT1, it can lead to the degradation of the target RNA, effectively reducing its presence in the cell. Preclinical studies have shown that ASOs targeting MALAT1 can significantly reduce tumor growth and metastasis in animal models.
Current research is actively investigating the potential of MALAT1-targeting ASOs in various preclinical models, including those for melanoma and breast cancer. While promising, challenges remain in translating these findings into standard clinical practice. Ensuring the targeted delivery of ASOs specifically to diseased cells while minimizing off-target effects in healthy tissues is a significant hurdle. Nevertheless, advancements in ASO chemistry and delivery systems are ongoing, making MALAT1 an active area of therapeutic development.