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Theranostics 2018; 8(10):2739-2751. doi:10.7150/thno.21477 This issue Cite

Research Paper

Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1

Jingying Cao^1,2,3, Xin Wang¹, Tao Dai⁴, Yuanzhong Wu¹, Meifang Zhang¹, Renxian Cao⁵, Ruhua Zhang¹, Gang Wang¹, Rou Jiang¹, Binhua P. Zhou^1,2, Jian Shi^6✉, Tiebang Kang^1✉

1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China.
2. Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
3. Department of Medicine Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, 410013, P. R. China.
4. Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University, Hunan Cancer Hospital, Changsha, 410013, P. R. China.
5. Institute of Clinical Medicine, the First Affiliated Hospital of University of South China, Hengyang, P. R. China.
6. Department of Pathology, School of Basic Medical Science; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou 510515, China

✉ Corresponding author: Tel.: +86 20 87343182; fax: +86 20 87343170. Email address: jianshismucom (J. Shi) or kangtborg.cn (T. Kang).

Abstract

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive.

Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients.

Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients.

Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells.

Keywords: ROR1, Twist, EMT, tumor metastasis, basal-like breast cancer (BLBC)

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