Dissertation
Optimizing liver cancer model selection through transcriptomic characterizations and uncovering tumor-suppressive long non-coding RNA FAM99A as a liver-specific translation regulator
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2025
DOI:
https://doi.org/10.17918/00010911
Abstract
Liver cancer research demands robust cellular models and molecular biomarkers that accurately reflect disease biology. We present a comprehensive dual investigation addressing both challenges through transcriptomic analyses of 541 samples spanning multiple liver cancer subtypes and cell lines. Using a signature of 2,523 highly variable genes, we identified distinct molecular profiles distinguishing cancer subtypes and their corresponding cell lines, determining optimal models for each disease type. We identified potential mischaracterizations, notably demonstrating HepG2 cells most closely resemble hepatoblastoma rather than their commonly reported hepatocellular carcinoma (HCC) origin, and revealed that physioxic primary hepatocyte culture conditions better preserve liver-specific expression programs. Building on these findings, we next conducted a systematic biomarker screening that identified FAM99A as a liver-specific long non-coding RNA significantly downregulated in HCC and other liver cancers, with progressive loss during hepatocyte de-differentiation. Through clinical data analyses, isoform characterization, colony formation assays, and RNA-seq, we established FAM99A's potential tumor suppressor function. GSEA revealed translation and ribosome biogenesis as the primary pathways affected by FAM99A overexpression, which we validated through protein synthesis assays. Analysis of TREX mass spectrometry data identified FAM99A's interaction with key translation initiation factors and RNA helicases, suggesting a liver-specific role in regulating translation to balance the organ's regenerative capacity and protein synthesis demands. Ultimately, this work identifies FAM99A as a strong candidate biomarker and translation regulator in hepatic biology while characterizing its fundamental roles. Understanding FAM99A's mechanisms carries significant clinical implications, establishing it as an attractive therapeutic target for novel liver cancer treatment strategies.
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Details
- Title
- Optimizing liver cancer model selection through transcriptomic characterizations and uncovering tumor-suppressive long non-coding RNA FAM99A as a liver-specific translation regulator
- Creators
- Nima Sarfaraz
- Contributors
- Michael Bouchard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 154 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022047421704721