Transcriptional Control of Hepatocellular Carcinoma Cells Aggressiveness by AAV2/8-Mediated Delivery of Human Centenarian-Associated SIRT6 N308K/A313S.
[BACKGROUND/OBJECTIVES] Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a chief cause of cancer-related mortality throughout the world.
APA
Vittal M, Liorni N, et al. (2026). Transcriptional Control of Hepatocellular Carcinoma Cells Aggressiveness by AAV2/8-Mediated Delivery of Human Centenarian-Associated SIRT6 N308K/A313S.. Cancers, 18(5). https://doi.org/10.3390/cancers18050812
MLA
Vittal M, et al.. "Transcriptional Control of Hepatocellular Carcinoma Cells Aggressiveness by AAV2/8-Mediated Delivery of Human Centenarian-Associated SIRT6 N308K/A313S.." Cancers, vol. 18, no. 5, 2026.
PMID
41827746
Abstract
[BACKGROUND/OBJECTIVES] Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and a chief cause of cancer-related mortality throughout the world. SIRT6 is a fundamental sirtuin that governs several disease processes encompassing inflammation and cancer, including HCC. Longevity in centenarian Ashkenazi Jews was recently associated to novel allelic variants of SIRT6 (N308K/A313S), which ameliorate genome maintenance and DNA repair, and suppress cancer cells. It is currently unknown whether the above-mentioned SIRT6 variants display divergent or similar roles in HCC pathogenesis, compared to the wild-type (WT) counterpart.
[METHODS] Our goal was to elucidate how these new centenarian-associated SIRT6 genetic variants may modulate HCC cell lines' (HepG2 and Huh-7) aggressiveness and behavior, using functional and transcriptomic approaches.
[RESULTS] We demonstrate that adeno-associated virus (AAV2/8)-mediated overexpression of centenarian-associated SIRT6 variants hampered HCC cell proliferation, with transcriptomic data showing the modulation of hallmark genes involved in the turnover of collagen/extracellular matrix (ECM). In addition, we found that AAV2/8-mediated overexpression of SIRT6 N308K/A313S decreased invasion and also increased stiffness in HCC cells, as measured by nanoindentation, in a more pronounced fashion compared to SIRT6 WT. Intracellular stiffness is a property of the cancer cells themselves, which, along with ECM invasiveness, plays a significant role in the progression of HCC.
[CONCLUSIONS] These data suggest that increased intracellular stiffening mirrors increased cell motility and invasive behavior; it can be indicative of suppressed cancer development and progression by the centenarian-associated SIRT6 N308K/A313S mutant.
[METHODS] Our goal was to elucidate how these new centenarian-associated SIRT6 genetic variants may modulate HCC cell lines' (HepG2 and Huh-7) aggressiveness and behavior, using functional and transcriptomic approaches.
[RESULTS] We demonstrate that adeno-associated virus (AAV2/8)-mediated overexpression of centenarian-associated SIRT6 variants hampered HCC cell proliferation, with transcriptomic data showing the modulation of hallmark genes involved in the turnover of collagen/extracellular matrix (ECM). In addition, we found that AAV2/8-mediated overexpression of SIRT6 N308K/A313S decreased invasion and also increased stiffness in HCC cells, as measured by nanoindentation, in a more pronounced fashion compared to SIRT6 WT. Intracellular stiffness is a property of the cancer cells themselves, which, along with ECM invasiveness, plays a significant role in the progression of HCC.
[CONCLUSIONS] These data suggest that increased intracellular stiffening mirrors increased cell motility and invasive behavior; it can be indicative of suppressed cancer development and progression by the centenarian-associated SIRT6 N308K/A313S mutant.