CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer.
CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer.
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DOI：
10.1038/s41419-023-05608-3
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发表时间：
2023-02-03
影响因子：
9
通讯作者：
Shin, Incheol
中科院分区：
文献类型：
--
作者：
Son, Seogho;Kim, Hyungjoo;Lim, Hogeun;Lee, Joo-hyung;Lee, Kyung-min;Shin, Incheol
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型。TNBC患者通常由于其快速生长和转移潜力而表现出不利的结果。在这里，我们发现CCN 3在TNBC患者中过表达。我们发现，CCN 3敲低在体外和体内减少了癌症干细胞的形成、转移和肿瘤生长。从机制上讲，CCN 3的消融降低了EGFR/MAPK通路的活性。转录组分析显示，CCN 3诱导糖蛋白非转移性黑色素瘤蛋白B（GPNMB）的表达，这反过来激活EGFR途径。对TCGA数据集的询问进一步支持CCN 3对GPNMB的转录调节。最后，我们发现CCN 3通过配体依赖性或非依赖性机制激活Wnt信号传导，这增加了小眼症相关转录因子（MITF）蛋白，一种诱导GPNMB表达的转录因子。总之，我们的研究结果证明了CCN 3在TNBC中的致癌作用，我们提出CCN 3作为TNBC的假定治疗靶点。
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC patients typically exhibit unfavorable outcomes due to its rapid growth and metastatic potential. Here, we found overexpression of CCN3 in TNBC patients. We identified that CCN3 knockdown diminished cancer stem cell formation, metastasis, and tumor growth in vitro and in vivo. Mechanistically, ablation of CCN3 reduced activity of the EGFR/MAPK pathway. Transcriptome profiling revealed that CCN3 induces glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, which in turn activates the EGFR pathway. An interrogation of the TCGA dataset further supported the transcriptional regulation of GPNMB by CCN3. Finally, we showed that CCN3 activates Wnt signaling through a ligand-dependent or -independent mechanism, which increases microphthalmia-associated transcription factor (MITF) protein, a transcription factor inducing GPNMB expression. Together, our findings demonstrate the oncogenic role of CCN3 in TNBC, and we propose CCN3 as a putative therapeutic target for TNBC.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
CCN3是与增强肝细胞癌干性和凝血相关的治疗靶点
影响因子：
4.6
作者：
Jia Q;Xue T;Zhang Q;Cheng W;Zhang C;Ma J;Bu Y;Yu S;Liu Q
通讯作者：
Liu Q
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
4.7
作者：
Chen, Po-Chun;Lin, Tien-Huang;Tang, Chih-Hsin
通讯作者：
Tang, Chih-Hsin
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM