MICALL2 promotes angiogenesis of colorectal cancer by regulating the EGFR/PI3K/AKT/KLF5/VEGFA axis.

Colorectal cancer (CRC) is a common malignancy with high incidence and mortality, and tumor angiogenesis plays a crucial role in its progression and metastasis. Although anti-angiogenic therapies are promising, their effectiveness is limited by side effects, drug resistance, and relapse, underscoring the urgent the need to explore novel mechanisms and targets underlying CRC angiogenesis. In this study, using single-cell RNA sequencing (scRNA-seq) and weighted gene co-expression network analysis (WGCNA), we found that MICALL2 is predominantly expressed in CRC epithelial cells and correlated with angiogenesis-related pathways, such as VEGFA/VEGFR2 signaling. This aligns with immunohistochemical results demonstrating a positive correlation between MICALL2 expression and microvessel density. Functionally, in vitro experiments showed that conditioned media from CRC cells overexpressing MICALL2 enhanced the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas MICALL2 knockdown produced the opposite effects. In vivo, chick chorioallantoic membrane (CAM) assays and xenograft models confirmed the pro-angiogenic role of MICALL2. Mechanistically, MICALL2 stabilizes EGFR by inhibiting lysosomal degradation, leading to activation of the PI3K/AKT pathway, which in turn upregulates the transcription factor KLF5 and subsequent VEGFA expression. Pharmacological inhibition of PI3K via LY294002 reversed MICALL2-induced angiogenesis. Therefore, MICALL2 facilitates CRC angiogenesis through the EGFR/PI3K/AKT/KLF5/VEGFA axis and may serve as a promising target for anti-angiogenic therapy.