Hypoxia-Mediated Complement 1q Binding Protein Regulates Metastasis and Chemoresistance in Triple-Negative Breast Cancer and Modulates the PKC-NF-κB-VCAM-1 Signaling Pathway

Targeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.

RNA-sequencing of TNBC cells under hypoxia was performed to identify C1QBP. The effect of hypoxia inducible factor 1 subunit alpha (HIF-1α) on C1QBP expression was investigated using chromatin immunoprecipitation (ChIP) assay. The role of C1QBP in mediating metastasis, chemoresistance to PTX, and regulation of metastasis-linked vascular cell adhesion molecule 1 (VCAM-1) expression were studied using in vitro and in vivo experiments. Clinical tissue microarrays were used to verify the correlation of C1QBP with the expression of HIF-1α, VCAM-1, and RELA proto-oncogene nuclear factor-kappa B subunit (P65).

We found that hypoxia-induced HIF-1α upregulated C1QBP. The inhibition of C1QBP notably blocked metastasis of TNBC cells and increased their sensitivity to PTX under hypoxic conditions. Depletion of C1QBP decreased VCAM-1 expression by reducing the amount of P65 in the nucleus and suppressed the activation of hypoxia-induced protein kinase C-nuclear factor-kappa B (PKC-NF-κB) signaling.immunohistochemistry (IHC) staining of the tissue microarray showed positive correlations between the C1QBP level and those of HIF-1α, P65, and VCAM-1.