How a Non-Coding RNA Opens New Doors for Treatment
By exploring the role of FAM83H-AS1 in lung adenocarcinoma, researchers are uncovering new therapeutic possibilities
In the intricate landscape of cancer research, scientists have long focused on mutations in protein-coding genes as the primary drivers of disease. But a revolutionary shift is underway, revealing a hidden layer of genetic regulation that plays a crucial role in cancer development. Enter the world of long non-coding RNAs (lncRNAs)—molecules that don't produce proteins but powerfully influence how cancer behaves.
Among these, FAM83H-AS1 has emerged as a key player in lung adenocarcinoma, the most common type of lung cancer. Recent research reveals this once-obscure genetic element not only drives cancer progression but may also represent a promising new therapeutic target, offering hope for improved treatments for this deadly disease 4 .
Traditional focus of cancer research, accounting for only ~2% of human genome.
Regulatory molecules that don't produce proteins but control gene expression.
To understand the significance of FAM83H-AS1, we must first appreciate what long non-coding RNAs are. Imagine your DNA as an extensive library containing recipe books. While some books provide full protein recipes (protein-coding genes), many others contain instructions that don't make actual dishes but instead tell the kitchen staff how to use the recipe books.
These are non-coding RNAs—they don't create proteins but regulate how genes are expressed and function. LncRNAs are particularly important because they can influence multiple aspects of cell behavior, and when their function goes awry, they can contribute to diseases like cancer.
Protein-Coding Genes
Non-Coding RNAs
Non-coding RNAs act as instructions for how to use protein-coding genes
The discovery of FAM83H-AS1's role in cancer began with systematic analyses of large cancer datasets. Researchers examining The Cancer Genome Atlas (TCGA) lung adenocarcinoma data noticed something striking: FAM83H-AS1 was consistently overexpressed in tumors compared to normal lung tissue, and this overexpression correlated strongly with poor patient survival 4 .
What makes FAM83H-AS1 particularly interesting is its regulation by chromosome 8q24 amplification, a common genetic alteration in cancers 1 5 . This region of the chromosome is duplicated, leading to increased copies and subsequent overexpression of FAM83H-AS1, which in turn drives cancer progression.
Research has revealed that FAM83H-AS1 contributes to lung cancer through several interconnected mechanisms:
Cancer cells with high FAM83H-AS1 levels multiply more rapidly, forming tumors more aggressively.
Apoptosis, or programmed cell death, is a natural defense against cancer. FAM83H-AS1 suppresses this process.
FAM83H-AS1 enhances the ability of cancer cells to invade surrounding tissues and migrate to distant sites.
Evidence suggests FAM83H-AS1 may contribute to resistance against targeted therapies 4 .
While our focus is on lung adenocarcinoma, it's noteworthy that FAM83H-AS1's oncogenic role isn't limited to this cancer type. Research has identified its overexpression in numerous other malignancies:
| Cancer Type | Expression Level | Clinical Significance |
|---|---|---|
| Gastric Cancer | Associated with poor prognosis | |
| Bladder Cancer | Promotes cell proliferation | |
| Breast Cancer | Correlates with tumor grade | |
| Colorectal Cancer | Contributes to chemoresistance | |
| Pancreatic Cancer | Associated with shorter survival | |
| Liver Cancer | Promotes metastasis |
This pattern across multiple cancer types suggests FAM83H-AS1 participates in fundamental processes that drive cancer progression broadly, making it an even more compelling target for therapeutic development.
To truly understand how FAM83H-AS1 works, let's examine a pivotal study published in Clinical and Translational Medicine in 2021 that uncovered its molecular mechanism 1 5 . This research employed a comprehensive approach to decipher how this lncRNA influences cancer cells.
They began by analyzing genomic, transcriptomic, and clinical data from TCGA lung adenocarcinoma datasets to identify promising lncRNA candidates.
Using zebrafish models, they tested the biological function of their leading candidate, FAM83H-AS1, in living organisms.
They employed techniques including RNA pull-down assays, RNA immunoprecipitation, and quantitative mass spectrometry to identify what proteins FAM83H-AS1 interacts with.
Finally, they used CRISPR interference (CRISPRi) and patient-derived tumor xenograft (PDTX) models to evaluate whether targeting FAM83H-AS1 could have therapeutic benefit.
The results were striking. Researchers discovered that FAM83H-AS1 binds to a protein called HNRNPK and enhances the translation of RAB8B and RAB14—two proteins known for their anti-apoptotic (cell survival-promoting) effects 1 5 .
FAM83H-AS1
HNRNPK
RAB8B/RAB14
FAM83H-AS1 binds to HNRNPK to enhance translation of anti-apoptotic proteins RAB8B and RAB14
Perhaps most importantly, when the researchers targeted FAM83H-AS1 in experimental models, they observed significant inhibition of lung adenocarcinoma progression, suggesting a genuine therapeutic potential.
| Experimental Measure | Effect of Reduction |
|---|---|
| Cell Proliferation | Decreased by >30% in 7/12 lung cancer cell lines |
| Apoptosis | Increased programmed cell death |
| Invasion Capacity | Reduced by 70% in PC-9 and H1650 cells |
| In vivo Tumor Growth | Significant inhibition in PDTX models |
| Patient Cohort | High Expression Association |
|---|---|
| TCGA LUAD | Shorter overall survival |
| Jiangsu Cancer Hospital | Poor prognosis |
| Independent Validation | Worse survival outcomes |
Understanding how researchers study FAM83H-AS1 requires familiarity with their experimental toolkit. Here are some of the crucial reagents and methods used in this field:
(CRISPR Interference)
Gene silencing without DNA cleavage for targeted inhibition of FAM83H-AS1 expression.
(RIP)
Identifies RNA-protein interactions, confirmed FAM83H-AS1 binding to HNRNPK.
(PDTX)
Human tumors grown in immunodeficient mice to test therapeutic targeting.
(RNA-Seq)
Comprehensive profiling of RNA expression to identify differential expression.
(siRNA)
Transient gene silencing for knockdown studies to determine function.
Measures RNA expression levels to validate overexpression in tumor samples.
The discovery of FAM83H-AS1's role in lung adenocarcinoma opens exciting therapeutic possibilities. Traditional drugs typically target proteins, but lncRNAs like FAM83H-AS1 represent a new class of targets.
These are short, synthetic nucleic acid strands designed to bind specifically to FAM83H-AS1 RNA, promoting its degradation or blocking its function.
Early studies in gastrointestinal cancers have shown that ASOs against FAM83H-AS1 can suppress tumor growth, particularly when combined with platinum-based chemotherapy 6 .
Evidence suggests that targeting FAM83H-AS1 may enhance the effectiveness of conventional treatments.
In one study, combining ASO-FAM83H-AS1 with oxaliplatin/cisplatin resulted in significantly improved tumor suppression compared to either treatment alone 6 .
The story of FAM83H-AS1 represents a paradigm shift in our understanding of cancer biology. It demonstrates that elements of our genome once considered "junk" play critical roles in disease pathogenesis. As a non-coding oncogenic driver, FAM83H-AS1 offers not only insight into the fundamental mechanisms of lung adenocarcinoma but also a promising therapeutic target that could potentially benefit patients with multiple cancer types.
While translating these discoveries into clinical treatments will require further research, the progress exemplifies how exploring the non-coding genome can unveil new opportunities for combatting cancer. As research continues, FAM83H-AS1 may well become both a biomarker for identifying aggressive cancers and a target for innovative treatments, ultimately improving outcomes for patients facing this challenging disease.
The journey of FAM83H-AS1 from obscurity to oncogenic prominence serves as a powerful reminder that there is still much to discover in human biology, and that these discoveries may hold the key to unlocking new approaches to some of medicine's most persistent challenges.