Low Expression of ARHGAP40 in Colorectal Cancer Facilitates Tumor Progression by Activating the RhoA Pathway

Abstract

: Background: Rho GTPase-activating protein 40 (ARHGAP40), downregulated in various tumors, including basal cell carcinoma, has an unclear role in colorectal cancer (CRC). This study aimed to elucidate the function and clinical significance of ARHGAP40 in CRC. Methods: ARHGAP40 expression in CRC tissues was evaluated by immunohistochemistry and analyzed in relation to clinicopathological features and patient survival. Gain-and loss-of-function experiments were performed in CRC cell lines to assess cell proliferation, apoptosis, migration, and invasion. RNA sequencing, co-immunoprecipitation, Ras homolog gene family member A (RhoA) activation assays, and rescue experiments were conducted to explore the underlying mechanism. Results: ARHGAP40 expression was significantly decreased in CRC tissues and cell lines. Low ARHGAP40 expression was associated with poor differentiation ( p < 0.001), deeper tumor invasion ( p = 0.004), lymph node metastasis ( p < 0.001), advanced TNM stage ( p < 0.001), and unfavorable prognosis in patients with CRC ( p < 0.05). Functional experiments showed that ARHGAP40 overexpression suppressed CRC cell proliferation, migration, and invasion, while promoting apoptosis, whereas ARHGAP40 knockdown exerted opposite effects. Mechanistically, ARHGAP40 interacted with RhoA and negatively regulated its activation. Moreover, restoration of RhoA activity partially reversed the effects of ARHGAP40 overexpression on CRC cell proliferation and apoptosis. Conclusions: ARHGAP40 is downregulated in CRC, and its loss may contribute to tumor progression, possibly through dysregulation of RhoA activity.