H19-miR-675-5p-CBL pathway (H19/miR-675/CBL axis)

The H19-miR-675-5p-CBL pathway is a significant regulatory axis that links long non-coding RNA (lncRNA) expression to the stability of receptor tyrosine kinases (RTKs). In this signaling network, the lncRNA H19 serves as a precursor for the microRNA miR-675-5p, which directly targets the mRNAs of the E3 ubiquitin ligases c-Cbl and Cbl-b (Vennin et al., 2015). Under normal conditions, these CBL proteins facilitate the ubiquitination and subsequent lysosomal degradation of activated RTKs like EGFR and c-Met. However, when the H19/miR-675 axis is overexpressed, CBL levels are suppressed, leading to the stabilization and sustained activation of these receptors. This overactivation triggers downstream oncogenic cascades, including the PI3K/AKT and MAPK/ERK pathways, which promote tumor cell proliferation, survival, and metastasis (Vennin et al., 2015; Yan et al., 2017). This pathway has been extensively studied in breast, gastric, and lung cancers, where it often correlates with poor prognosis and drug resistance. Therapeutic interventions currently being explored include natural compounds like Huaier extract and experimental RNA-interference tools designed to disrupt this oncogenic signaling loop (Zhai et al., 2017; Pan et al., 2021).

Other names

H19/miR-675/c-Cbl axisH19/miR-675/Cbl-b axisH19-miR-675-CBL signaling pathwaylncRNA H19/miR-675/CBL regulatory network

H19 functions as a precursor for miR-675-5p, which post-transcriptionally silences the E3 ubiquitin ligases c-Cbl and Cbl-b, thereby preventing the degradation of receptor tyrosine kinases (e.g., EGFR, c-Met) and promoting oncogenic AKT and ERK signaling.