Sequential Logic-Gated Prioritization of microRNA Networks Identifies DKK1 as a Candidate Associated With Metabolic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is projected to become the leading cause of hepatocellular carcinoma (HCC) worldwide. Unlike fibrosis in other organs, liver fibrosis carries a higher risk of malignant transformation, suggesting that hepatic microenvironmental signaling promotes oncogenesis and metastasis. Our overarching hypothesis is that MASLD-HCC and metastasis are associated with reduced expression of tumor-suppressive microRNAs and increased expression of oncogenes. We undertook an in silico, logic-gated, prioritization strategy integrating MASLD-HCC-associated microRNA networks, HCC biomarker-associated microRNA networks, tumor suppressor scoring, and expression analyses to identify candidates associated with MASLD-HCC and metastasis. Sequential Boolean AND logic gating identified hsa-miR-101-3p, -206, and -613, each with tumor-suppressive activity and reduced expression in HCC and other cancers. All three microRNAs converged on a single node, Dickkopf-related protein 1(dkk1). Previous studies have associated DKK1 with migration, invasion, and angiogenesis, promoting tumor aggressiveness, vascular invasion, pulmonary and lymphatic metastasis, recurrence, and poor overall survival. Integration in silico of network biology, transcriptomic analysis, and literature-derived mechanistic evidence supports a hypothesis for a loss-of-control model in which MASLD-HCC is associated with reduced expression of tumor-suppressive microRNAs and increased expression of oncogenic DKK1.