Hao Wu1,2,3, Yijun Chu2,3,4, Shanshan Sun2,3,4, Guozheng Li2,3,4, Shouping Xu2,3,4, Xianyu Zhang2,3,4, Yongdong Jiang2,3,4, Song Gao2,3,4, Qin Wang1,2,3, Jian Zhang4, Da Pang1,2,3,4. 1. Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, China. 2. Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, Harbin, China. 3. Heilongjiang Academy of Medical Sciences, Harbin, China. 4. Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Abstract
OBJECTIVES: Complement 1q binding protein (C1QBP/HABP1/p32/gC1qR) has been found to be overexpressed in triple-negative breast cancer (TNBC). However, the underlying mechanisms of high C1QBP expression and its role in TNBC remain largely unclear. Hypoxia is a tumor-associated microenvironment that promotes metastasis and paclitaxel (PTX) chemoresistance in tumor cells. In this study, we aimed to assess C1QBP expression and explore its role in hypoxia-related metastasis and chemoresistance in TNBC. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: Targeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.
OBJECTIVES: Complement 1q binding protein (C1QBP/HABP1/p32/gC1qR) has been found to be overexpressed in triple-negative breast cancer (TNBC). However, the underlying mechanisms of high C1QBP expression and its role in TNBC remain largely unclear. Hypoxia is a tumor-associated microenvironment that promotes metastasis and paclitaxel (PTX) chemoresistance in tumor cells. In this study, we aimed to assess C1QBP expression and explore its role in hypoxia-related metastasis and chemoresistance in TNBC. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSION: Targeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.
Authors: Valentina Fogal; Ivan Babic; Ying Chao; Sandra Pastorino; Rajesh Mukthavaram; Pengfei Jiang; Yoon-Jae Cho; Sandeep C Pingle; John R Crawford; David E Piccioni; Santosh Kesari Journal: Oncotarget Date: 2015-01-20
Authors: A Moles; J A Butterworth; A Sanchez; J E Hunter; J Leslie; H Sellier; D Tiniakos; S J Cockell; D A Mann; F Oakley; N D Perkins Journal: Oncogene Date: 2016-02-08 Impact factor: 9.867