ADAMTS3 Promotes Hepatocellular Carcinoma Cell Growth and Migration Through TGF-β:TGFBR2 Signaling

Early diagnosis of hepatocellular carcinoma (HCC) still represents a significant challenge, particularly in the context of etiological shift toward obesity and non-viral liver disease-associated HCC. Through intersection-based analysis of independent transcriptomic datasets comprising healthy controls, individuals with obesity or NAFLD, and HCC patients with viral or non-viral etiologies, we prioritized ADAMTS3, a secreted protein, for further investigation of its functional and mechanistic relevance to HCC. ADAMTS3 was upregulated in HCC and demonstrated transcriptomic discrimination between HCC and non-HCC populations. Notably, in the validation cohort, ADAMTS3 retained discriminative capacity in clinically defined alpha-fetoprotein-negative HCC patients. Functionally, ADAMTS3 knockdown impaired cell proliferation, clonogenicity, and migration, while inducing apoptosis and cell-cycle arrest. Reintroduction of ADAMTS3 partially rescued these cellular effects. Mechanistically, ADAMTS3 promotes HCC cell growth and migration through TGF-β:TGFBR2 signaling. ADAMTS3 knockdown increased extracellular TGF-β and downstream SMAD phosphorylation. Neutralization of extracellular TGF-β alleviated growth inhibition caused by ADAMTS3 knockdown. Consistently, TGFBR2 knockdown partially restored the cell growth and migration suppressed by ADAMTS3 knockdown. We also developed a DNA origami-based SERS aptasensor targeting ADAMTS3, achieving highly sensitive detection of ADAMTS3 down to 10−12 M with strong quantitative capability (R2 = 0.914). Together, our findings support a role for ADAMTS3 in promoting HCC cell growth and migration and provide a basis for further investigation of its relevance to HCC biomarker development. The DNA origami-based SERS aptasensor provides a sensitive analytical approach for future studies of circulating or serum ADAMTS3.