复旦发现乳腺癌生长转移双向靶点
关于乳腺癌从局部病变到浸润和最终转移的恶化过程，其分子学基础尚不明确。
2018年9月15日，美国癌症研究学会（AACR）官方期刊《癌症研究》正式发表复旦大学附属肿瘤医院肿瘤研究所乳腺癌研究所生物医学研究院李大强、邵志敏等学者的研究报告，发现FBXO22对于乳腺癌的进展过程，既有促肿瘤生长作用，又有抗肿瘤转移作用。
该研究发现FBXO22对于乳腺肿瘤的生长和转移可以发挥双向作用。原发乳腺肿瘤的FBXO22表达水平上调，并且促进体外细胞增殖和集落形成以及体内异种移植肿瘤形成。令人惊讶的是，FBXO22可以抑制体外的上皮→间质转化、细胞运动、浸润以及体内的转移性肺定植。临床数据表明，FBXO22表达水平与有利的临床结局相关，证实了转移（而非原发癌）是乳腺癌患者死亡风险主要决定因素的观点。机制研究进一步表明，FBXO22通过靶向上皮→间质转化和乳腺癌转移的主要调节因子SNAIL，从而产生泛素所致糖原合成酶激酶3β（GSK3β）磷酸化依赖方式蛋白酶体降解的抗转移作用。重要的是，SNAIL表达可以保护FBXO22对上皮→间质转化、细胞迁移和浸润的抑制作用。来自患者的FBXO22结构区残基52（W52R）色氨酸→精氨酸突变，可以妨碍FBXO22与SKP1滞蛋白1复合物的结合，并且阻断FBXO22所致SNAIL降解，从而抵消FBXO22对细胞迁移、浸润和转移的抑制能力。
因此，该研究结果表明，FBXO22对于乳腺肿瘤的生长和转移，可以发挥出人意料的双向作用，并且阐明了FBXO22对于乳腺癌进展的致癌突变机制。
Cancer Res. 2018 Sep 15;78(18):5274-5286.
FBXO22 Possesses Both Protumorigenic and Antimetastatic Roles in Breast Cancer Progression.
Sun R, Xie HY, Qian JX, Huang YN, Yang F, Zhang FL, Shao ZM, Li DQ.
Institutes of biomedical sciences, Fudan University; Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University; Fudan University; Cancer Institute, Fudan University; Breast Cancer Institution, Cancer Hospital,Fudan University; Cancer Institute and Institute of Biomedical Sciences, Fudan University.
The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation in vitro and xenograft tumorigenicity in vivo. Surprisingly, FBXO22 suppressed epithelial–mesenchymal transition (EMT), cell motility, and invasiveness in vitro and metastatic lung colonization in vivo. Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation–dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1–Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression.
SIGNIFICANCE: These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis.
PMID: 29945959
PII: canres.3647.2017
DOI: 10.1158/0008-5472.CAN-17-3647
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