PDF(Pubmed)
Abstract：
GNA13 (Gα13) is one of two alpha subunit members of the G12/13 family of heterotrimeric G-proteins which mediate signaling downstream of GPCRs. It is known to be essential for embryonic development and vasculogenesis and has been increasingly shown to be involved in mediating several steps of cancer progression. Recent studies found that Gα13 can function as an oncogene and contributes to progression and metastasis of multiple tumor types, including ovarian, head and neck and prostate cancers. In most cases, Gα12 and Gα13, as closely related α-subunits in the subfamily, have similar cellular roles. However, in recent years their differences in signaling and function have started to emerge. We previously identified that Gα13 drives invasion of Triple Negative Breast Cancer (TNBC) cells in vitro. As a highly heterogenous disease with various well-defined molecular subtypes (ER+ /Her2-, ER+ /Her2+, Her2+, TNBC) and subtype associated outcomes, the function(s) of Gα13 beyond TNBC should be explored. Here, we report the finding that low expression of GNA13 is predictive of poorer survival in breast cancer, which challenges the conventional idea of Gα12/13 being universal oncogenes in solid tumors. Consistently, we found that Gα13 suppresses the proliferation in multiple ER+ breast cancer cell lines (MCF-7, ZR-75-1 and T47D). Loss of GNA13 expression drives cell proliferation, soft-agar colony formation and in vivo tumor formation in an orthotopic xenograft model. To evaluate the mechanism of Gα13 action, we performed RNA-sequencing analysis on these cell lines and found that loss of GNA13 results in the upregulation of MYC signaling pathways in ER+ breast cancer cells. Simultaneous silencing of MYC reversed the proliferative effect from the loss of GNA13, validating the role of MYC in Gα13 regulation of proliferation. Further, we found Gα13 regulates the expression of MYC, at both the transcript and protein level in an ERα dependent manner. Taken together, our study provides the first evidence for a tumor suppressive role for Gα13 in breast cancer cells and demonstrates for the first time the direct involvement of Gα13 in ER-dependent regulation of MYC signaling. With a few exceptions, elevated Gα13 levels are generally considered to be oncogenic, similar to Gα12. This study demonstrates an unexpected tumor suppressive role for Gα13 in ER+ breast cancer via regulation of MYC, suggesting that Gα13 can have subtype-dependent tumor suppressive roles in breast cancer.
摘要：
GNA13(Gα13)是介导GPCRs下游信号传导的异三聚体G蛋白G12/13家族的两个α亚基成员之一。已知它对于胚胎发育和血管发生是必不可少的，并且越来越多地显示出参与介导癌症进展的几个步骤。最近的研究发现,Gα13可以作为癌基因发挥作用,促进多种肿瘤类型的进展和转移,包括卵巢,头颈部和前列腺癌。在大多数情况下,Gα12和Gα13作为亚家族中密切相关的α亚基，具有类似的细胞作用。然而,近年来，它们在信号和功能上的差异已经开始显现。我们先前确定Gα13在体外驱动三阴性乳腺癌(TNBC)细胞的侵袭。作为一种高度异质性的疾病，具有各种明确定义的分子亚型（ER/Her2-，ER+/Her2+,Her2+,TNBC)和亚型相关结果，应探索Gα13超越TNBC的功能。这里,我们报告了以下发现：GNA13的低表达预示着乳腺癌患者的生存率较差，这挑战了Gα12/13是实体瘤中通用癌基因的传统想法。始终如一，我们发现Gα13抑制多种ER+乳腺癌细胞系(MCF-7,ZR-75-1和T47D)的增殖。GNA13表达的缺失驱动细胞增殖，原位异种移植模型中的软琼脂集落形成和体内肿瘤形成。为了评估Gα13的作用机制，我们对这些细胞系进行了RNA测序分析,发现GNA13缺失导致ER+乳腺癌细胞中MYC信号通路上调.MYC的同时沉默逆转了GNA13丢失的增殖作用，验证了MYC在Gα13增殖调节中的作用。Further,我们发现Gα13调节MYC的表达,在转录本和蛋白质水平上以ERα依赖性方式。一起来看,我们的研究为乳腺癌细胞中Gα13的肿瘤抑制作用提供了第一个证据,并首次证明了Gα13直接参与ER依赖性MYC信号调节.除了少数例外,升高的Gα13水平通常被认为是致癌的，类似于Gα12。这项研究表明，通过调节MYC，Gα13在ER+乳腺癌中具有意想不到的肿瘤抑制作用，提示Gα13在乳腺癌中具有亚型依赖性肿瘤抑制作用。
