ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer
Zhi-Hua Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorMei-Ling Chen
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorQi Zhang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Department of Ultrasound, The Fifth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorYu Zhang
Department of Pathology, SYSUCC, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorXin An
Department of Medical Oncology, SYSUCC, Guangzhou, China
Search for more papers by this authorYi-Ling Luo
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorXue-Min Liu
Section 3 of Internal Medicine, Guangzhou Medical University Affiliated Cancer Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorShang-Xin Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorQian Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorTing Yang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorYan-Min Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorBin-Liu Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorAi-Jun Zhou
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorMan-Zhi Li
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorYu-Jie Liu
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
Search for more papers by this authorZe-Xian Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorCorresponding Author
Qian Zhong
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Correspondence to: Qian Zhong, E-mail: [email protected]Search for more papers by this authorZhi-Hua Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorMei-Ling Chen
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorQi Zhang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Department of Ultrasound, The Fifth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorYu Zhang
Department of Pathology, SYSUCC, Guangzhou, China
Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work.Search for more papers by this authorXin An
Department of Medical Oncology, SYSUCC, Guangzhou, China
Search for more papers by this authorYi-Ling Luo
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorXue-Min Liu
Section 3 of Internal Medicine, Guangzhou Medical University Affiliated Cancer Hospital, Guangzhou, Guangdong, China
Search for more papers by this authorShang-Xin Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorQian Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorTing Yang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorYan-Min Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorBin-Liu Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorAi-Jun Zhou
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorMan-Zhi Li
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorYu-Jie Liu
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
Search for more papers by this authorZe-Xian Liu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Search for more papers by this authorCorresponding Author
Qian Zhong
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China
Correspondence to: Qian Zhong, E-mail: [email protected]Search for more papers by this authorAbstract
Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In our study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP-seq and RNA-seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation.
Abstract
What's new?
ZIC family members regulate neural development but have also been implicated in the development of various tumors. Here the authors report downregulation of ZIC2 in breast cancer cells. Low expression of ZIC2 correlated with poor outcome in breast cancer patients and served as an independent prognostic marker. The transcription factor STAT3 was identified as a potential target for ZIC2, and inhibition of STAT3 abrogated the oncogenic effects induced by decreased ZIC2 expression. STAT3 inhibitors might provide an alternative option for women with breast cancer showing ZIC2 downregulation.
Conflict of interest
The authors of this manuscript have no conflict of interests in relation to the work described.
Supporting Information
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