Liver-specific lncRNA FAM99A may be a tumor suppressor and promising prognostic biomarker in hepatocellular carcinoma

Abstract

Background Increasing evidence shows that liver-specific long non-coding RNAs (lncRNAs) play important roles in the development of hepatocellular carcinoma (HCC). We identified a novel liver-specific lncRNA, FAM99A, and examined its clinical significance and biological functions in HCC. Methods The expression level and clinical value of FAM99A in HCC were examined using The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases, and were further verified using quantitative real-time polymerase chain reaction (qRT–PCR) in our HCC cohort. Univariate and multivariate Cox proportional hazards regression models were also applied to identify independent prognostic indicators for HCC patients. Cell counting kit-8, colony formation, and Transwell assays were performed to evaluate the effects of FAM99A on the proliferation, migration, and invasion abilities of HCC cells in vitro. A subcutaneous xenograft tumor model was implemented to determine the effect of FAM99A on the tumor growth of HCC cells in vivo. RNA pull-down and mass spectrometry assays were performed to reveal the potential molecular mechanisms of FAM99A in HCC. Results The three public online databases and qRT–PCR data showed that FAM99A was frequently downregulated in HCC tissues and inversely correlated with microvascular invasion and advanced histological grade of HCC patients. Kaplan–Meier survival analysis indicated that decreased FAM99A was significantly associated with poor overall survival of HCC patients based on TCGA database (P = 0.040), ICGC data portal (P < 0.001), and our HCC cohort (P = 0.010). A multivariate Cox proportional hazards regression model based on our HCC cohort suggested that FAM99A was an independent prognostic factor of overall survival for HCC patients (hazard ratio: 0.425, P = 0.039). Upregulation of FAM99A suppressed the proliferation, colony formation, migration, and invasion capacities of HCC cells in vitro, and knockdown of FAM99A had the opposite effects. A subcutaneous xenograft tumor model demonstrated that overexpression of FAM99A significantly inhibited the tumor growth of HCC cells in vivo. Seven tumor-related proteins (PCBP1, SRSF5, SRSF6, YBX1, IGF2BP2, HNRNPK, and HNRNPL) were recognized as possible FAM99A-binding proteins by the RNA pull-down and mass spectrometry assays. Conclusion Our results suggest that FAM99A exerts cancer-inhibiting effects on HCC progression, and it may be a promising prognostic indicator for HCC patients.

Influence of Long Non-Coding RNA in the Regulation of Cancer Stem Cell Signaling Pathways

“…This maintains CSC self-renewal capabilities along with high tumorigenic activities [ 225 ]. In liver cancer, lncRNA FAM99A was seen to act as a tumor suppressor, and its upregulation was seen to reduce colony formation, proliferation, and invasion of HCC cells making it a possible prognostic marker in HCC [ 226 ]. As lncRNA HDAC2 expression profiles are directly proportional to the severity of HCC, it may also act as a diagnostic marker during initial stages and a promising drug target during increased expression levels.…”

Finding potential lncRNA–disease associations using a boosting-based ensemble learning model

“…lncRNAs have been in the clinical use as prognostic biomarkers of many complex diseases, including cancers (Tang et al, 2022;Huo et al, 2021). For example, liver-specific lncRNA FAM99A plays a cancerinhibiting role in hepatocellular carcinoma and might serve as its prognostic biomarker (Mo et al, 2022). Exosomal RP5-977B1 might be a diagnostic biomarker of non-small-cell lung cancer (NSCLC) (Min et al, 2022).…”

In silico analysis of the association between long non‐coding RNA family with sequence similarity 99 member A (FAM99A) and hepatic cancer

“…The family with sequence similarity 99 member A (FAM99A) gene was identified. Very recently, Mo et al reported the suppressor and prognostic effects of FAM99A on hepatocellular carcinoma (HCC) [8]. However, the deeper molecular mechanism remains unclear.…”