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ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis
Genes & Diseases ( IF 6.8 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.gendis.2020.01.015
Valery Adorno-Cruz 1, 2 , Andrew D Hoffmann 2 , Xia Liu 2, 3 , Nurmaa K Dashzeveg 2 , Rokana Taftaf 2 , Brian Wray 4 , Ruth A Keri 1, 5 , Huiping Liu 2, 6, 7, 8
Affiliation  

Cancer metastasis is largely incurable and accounts for 90% of breast cancer deaths, especially for the aggressive basal-like or triple negative breast cancer (TNBC). Combining patient database analyses and functional studies, we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis, such as miR-206 that inhibits stemness and metastasis of TNBC. Here we report that the integrin receptor CD49b-encoding ITGA2, a direct target of miR-206, promotes breast cancer stemness and metastasis. ITGA2 knockdown suppressed self-renewal related mammosphere formation and pluripotency marker expression, inhibited cell cycling, compromised migration and invasion, and therefore decreased lung metastasis of breast cancer. ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1. RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism, including CCND1 and ACLY as representative targets, respectively. Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells. Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest. ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels. CCND1 knockdown further mimics ITGA2 knockdown in abolishing lung colonization of breast cancer cells. We identified that the low levels of miR-206 as well as high expression levels of ITGA2, ACLY and CCND1 are associated with an unfavorable relapse-free survival of the patients with estrogen receptor-negative or high grade breast cancer, especially basal-like or TNBC, possibly serving as potential biomarkers of cancer stemness and therapeutic targets of breast cancer metastasis.



中文翻译:

ITGA2促进ACLY和CCND1的表达以增强乳腺癌干细胞和转移

癌症转移在很大程度上是无法治愈的,占乳腺癌死亡的 90%,尤其是侵袭性基底样乳腺癌或三阴性乳腺癌 (TNBC)。结合患者数据库分析和功能研究,我们检查了整合素家族成员与临床结果的关联,以及它们与先前确定的转移的 microRNA 调节因子(例如抑制 TNBC 干性和转移的 miR-206)的联系。在此,我们报道编码整合素受体 CD49b 的ITGA2(miR-206 的直接靶标)可促进乳腺癌干细胞性和转移。ITGA2敲低抑制了自我更新相关的乳腺球的形成和多能性标志物的表达,抑制了细胞周期,损害了迁移和侵袭,从而减少了乳腺癌的肺转移。ITGA2过表达逆转了 miR-206 引起的 G1 期细胞周期停滞。RNA测序分析显示,ITGA2敲低会抑制与细胞周期调节和脂质代谢相关的基因,包括分别作为代表性靶标的CCND1ACLY 。CCND1ACLY的敲低可抑制乳腺癌细胞的乳腺球形成。CCND1的过表达可挽救ITGA2敲低诱导的细胞周期停滞的表型。ACLY编码的 ATP 柠檬酸裂解酶对于维持细胞乙酰辅酶 A 水平至关重要。CCND1敲低进一步模仿ITGA2敲低,消除乳腺癌细胞的肺部定植。我们发现, miR-206的低水平以及ITGA2ACLYCCND1的高表达水平与雌激素受体阴性或高级别乳腺癌患者的不利无复发生存相关,特别是基底样或高级别乳腺癌患者。 TNBC,可能作为癌症干性的潜在生物标志物和乳腺癌转移的治疗靶点。

更新日期:2020-02-01
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