Xiyuan Qin,Kai Kang,Bowen Zhu,Yujie Shi,Shoushan Bu
Introduction and aims Oral squamous cell carcinoma (OSCC), frequently observed in the head and neck region, possesses mechanisms that have yet to be thoroughly clarified. Poor prognosis in OSCC is closely linked to the polarization of macrophages toward the M2 phenotype. Complement component 1q subcomponent-binding protein (C1QBP), a versatile protein commonly dysregulated in OSCC, has an unclear association with M2 macrophages. Methods Immunohistochemical (IHC) staining was conducted to determine the relationship between C1QBP expression and M2 macrophage infiltration. Flow cytometry (FC) and enzyme-linked immunosorbent assay (ELISA) were employed to explore the functional role of C1QBP in macrophages polarization. Furthermore, RNA sequencing combined with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were utilized to verify the increased expression of TNF receptor-associated factor 2 (TRAF2) and C-C motif chemokine 2 (CCL2). Additional validation of these findings was performed through in vivo experiments. Results A negative correlation was identified between C1QBP expression and CD206, a representative marker of M2 macrophages. Decreased levels of C1QBP in OSCC cells enhanced macrophage polarization toward the M2 phenotype and facilitated tumor progression by activating pivotal elements of the tumor necrosis factor (TNF) signaling pathway, notably TRAF2 and CCL2. Conclusion These findings suggest that C1QBP modulates the polarization of macrophages toward the M2 phenotype via the TRAF2-CCL2 signaling axis, thus contributing to OSCC malignancy progression. Consequently, targeting C1QBP to regulate M2 macrophage polarization may provide a promising therapeutic avenue for OSCC management.
A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.
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