Effect of deplation of vtRNA1-1 and vtRNA1-2 on gene expression in Huh7 hepatocellular carcinoma cells

Non-coding RNAs (ncRNAs) are pivotal in tumorigenesis and cancer progression, and recent evidence highlights the class of human vault RNAs as important regulators of cellular homeostasis. The human genome encodes four vtRNA paralogs that are differentially expressed in cancer tissues and have thus been implicated in tumor onset and progression. The so far best studied paralog of the vault RNA family, vtRNA1-1, is involved in crucial cellular processes such as resistance to apoptosis, regulation of autophagy, control of lysosomal biogenesis, and drug resistance. In this study, we present a comprehensive characterization of a vtRNA1-2 knockout (KO) hepatocellular carcinoma cell line, marking the first detailed research study on this specific vtRNA paralog. Our findings indicated that the absence of vtRNA1-2 resulted in reduced viability and proliferation of cancer cells, by modulating the MAPK signaling pathway. Significantly, vtRNA1-2 KO cells displayed impaired motility, leading to a marked reduction in the invasiveness of malignant cells. Intriguingly, vtRNA1-2, unlike the vtRNA1-1 paralog, did not affect autophagy or lysosomal activity. Instead, our data demonstrate that vtRNA1-2 is critically involved in angiogenesis, a key process in tumor progression, by reducing vascular endothelial growth factor A secretion and inhibiting tube formation. These insights revealed a distinct role of vtRNA1-2 in tumorigenesis and positioned it as a promising target for the development of novel anti-cancer therapies. Our study advances the understanding of vault RNAs in cancer biology and strongly suggests that each vtRNA paralog possesses a unique role, rather than being mere molecular doppelgangers.