STOML2 promotes hepatocellular carcinoma cell proliferation, invasion and migration by activating the PI3K/AKT signaling pathway (Review)

Stomatin-like protein 2 (STOML2) has emerged as a key oncoprotein in hepatocellular carcinoma (HCC), with its regulation being associated with tumor progression and poor patient prognosis. The present mechanistic review delineates how STOML2 functions as a central hub to promote HCC malignancy, which is primarily through constitutive activation of the PI3K/AKT signaling pathway. Direct mechanisms are detailed, including how STOML2 binds to the PI3K p85 subunit to stabilize the PI3K complex, promoting indirect modulations. These include potential interactions with receptor tyrosine kinases and negative regulators, such as PTEN, a number of which, while plausible, await definitive validation in HCC-specific models. The subsequent activation of the PI3K/AKT cascade by STOML2 drives key hallmarks of cancer, enhancing cell proliferation, suppressing apoptosis, potentiating invasion and metastasis through epithelial-mesenchymal transition, and contributing to chemotherapy resistance. Furthermore, the present review summarizes the upstream regulatory networks controlling STOML2, encompassing transcriptional, epigenetic and post-translational mechanisms, in addition to evaluating the therapeutic potential of targeting the STOML2/PI3K/AKT axis. Through integrating established evidence with clearly defined knowledge gaps, the present review provides a foundational framework for future research and the development of STOML2-directed diagnostic and therapeutic strategies for HCC.