Endocrine Abstracts

JOINT1000

Background: The SMG7 factor plays a key role in the nonsense-mediated mRNA decay (NMD), a cellular pathway that removes mRNAs containing common errors, such as premature termination codons (PTCs), to prevent their translation. Numerous NMD targets are involved in cellular stress responses. Additionally, SMG7 supports cell survival following genotoxic stress by activating the ATR-Chk1 pathway. Chronic exposure to lipotoxic free fatty acids (FFAs) in liver disease contributes to cellular stress and liver damage. This study focuses on investigating the role of SMG7 in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC).

Method: Expression (mRNA) of 22 NMD components was analyzed in two retrospective HCC cohorts (cohort 1 [n=89 HCC and non-tumor paired adjacent tissues (NTAT)] by microfluidic-based qPCR array and cohort 2 [n=31 HCC and n=31 NTAT] by RNA-seq), and validated in six external cohorts with healthy, MASLD, MASH, HCC, and/or NTAT samples. GSEA enrichment analysis was performed. Human (THLE2) and mouse primary hepatocytes (MPH) were treated with FFAs. Pharmacological (NMDI14, which blocks SMG7-UPF1 interaction) and genetic modulation of SMG7 were carried out in two liver-derived cell lines (Hep3B and SNU-387) to explore the functional effects in vitro.

Results: SMG7 is consistently overexpressed in samples of MASH, HCC, and MASH-derived HCC. In addition, hallmark pathways related to proliferation (mitotic spindle, G2M checkpoint, and E2F targets) are enriched in tumor samples with high SMG7 expression in the retrospective cohort 2 and an external cohort (TCGA or GSE164760). Furthermore, SMG7 (mRNA) expression was stimulated by FFAs (palmitate) in THLE2 and MPH cells, and its overexpression in liver cell lines enhances proliferation, as well as colony and tumorspheres formation. In contrast, SMG7 silencing reduced the proliferation and migration of SNU-387 cells, while having minimal functional effects on Hep3B cells, possibly due to a compensatory increase in UPF1, another key NMD factor. Notably, co-silencing SMG7 and UPF1 decreased tumor aggressiveness in both HCC cell lines. Consistently, treatment with NMDI14 led to a reduction in the aggressiveness of the HCC cell lines, while having no impact on MPH viability but reducing THLE2 proliferation.

Conclusion: The SMG7 factor could have a key role in the progression of MASLD-HCC, potentially opening new avenues for identifying biomarkers and/or therapeutic targets for these conditions.FundingsISCIII (FI21/00141, PI23/00652, MV23/00068; co-funded by the European Union), JdA (PEMP-0036-2020, PI-0046-2024, BIO-0139), FSEEN and CIBERobn/CIBERehd.