The lncRNA-miRNA-Hippo axis as a driver of cancer metastasis: A systematic review of mechanisms and clinical implications

Background The Hippo signaling pathway is a crucial regulator of organ size and tissue homeostasis, and its dysregulation is frequently implicated in cancer. Long non-coding RNAs (lncRNAs) have emerged as key modulators of this pathway through the competing endogenous RNA (ceRNA) network. However, a comprehensive synthesis of the lncRNA-miRNA-Hippo axis in cancer is lacking. This systematic review aimed to elucidate the regulatory mechanisms and clinical implications of this axis. Methods A systematic search was conducted across major electronic databases for studies published between 2017 and 2025. Studies were screened based on predefined inclusion criteria, focusing on the interaction of lncRNAs and miRNAs with core Hippo pathway components (e.g., YAP, TAZ, LATS1/2) in human cancers. Results 44 studies were included in this review. The analysis revealed a complex regulatory network wherein lncRNAs predominantly function as oncogenes. The majority of identified axes involved lncRNAs sponging specific miRNAs to relieve the repression on YAP or TAZ, thereby promoting cell proliferation, migration, invasion, and chemotherapy resistance. Crucially, this regulatory axis plays a pivotal role in driving cancer metastasis and epithelial-mesenchymal transition (EMT). Conversely, a subset of lncRNAs acted as tumor suppressors by sponging miRNAs to upregulate upstream kinases such as LATS1/2, thereby inhibiting Hippo pathway activity. Clinically, the dysregulation of these lncRNAs was consistently associated with poor prognosis and advanced tumor stages. Conclusion The lncRNA-miRNA-Hippo axis plays a pivotal role in the pathogenesis of cancer and in driving cancer metastasis. These findings highlight the potential of lncRNAs as diagnostic biomarkers and suggest that targeting the ceRNA network offers a promising therapeutic strategy for restoring Hippo pathway function in malignancies.