SOX4 promotes the growth and metastasis of breast cancer

Jing Zhang; Chunhua Xiao; Zhenbo Feng; Yun Gong; Baohua Sun; Zhongqi Li; Yimin Lu; Xiaojie Fei; Weizhu Wu; Xiaoping Sun; Lisong Teng

doi:10.1186/s12935-020-01568-2

SOX4 promotes the growth and metastasis of breast cancer

Cancer Cell Int. 2020 Sep 29:20:468. doi: 10.1186/s12935-020-01568-2. eCollection 2020.

Authors

Jing Zhang^{1

2}, Chunhua Xiao^{2

3}, Zhenbo Feng^{2

4}, Yun Gong², Baohua Sun², Zhongqi Li¹, Yimin Lu¹, Xiaojie Fei¹, Weizhu Wu⁵, Xiaoping Sun², Lisong Teng¹

Affiliations

¹ Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310003 People's Republic of China.
² Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA.
³ First Department of Breast Cancer, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, 1 Huan-Hu Xi Road, Ti-Yuan Bei, He Xi, Tianjin, 300060 People's Republic of China.
⁴ Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, Guangxi 530021 People's Republic of China.
⁵ Department of Breast and Thyroid Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang 315000 People's Republic of China.

Abstract

Purpose: Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo.

Methods: We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging.

Results: SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo. It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel.

Conclusions: SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

Keywords: Breast cancer; CXCR7; Growth; Metastasis; SOX4.