Hasumi Yukiko, Baba Masaya, Ajima Rieko, Hasumi Hisashi, Valera Vladimir A, Klein Mara E, Haines Diana C, Merino Maria J, Hong Seung-Beom, Yamaguchi Terry P, Schmidt Laura S, Linehan W Marston
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18722-7. doi: 10.1073/pnas.0908853106. Epub 2009 Oct 22.
Germline mutations in the BHD/FLCN tumor suppressor gene predispose patients to develop renal tumors in the hamartoma syndrome, Birt-Hogg-Dubé (BHD). BHD encodes folliculin, a protein with unknown function that may interact with the energy- and nutrient-sensing AMPK-mTOR signaling pathways. To clarify BHD function in the mouse, we generated a BHD knockout mouse model. BHD homozygous null (BHD(d/d)) mice displayed early embryonic lethality at E5.5-E6.5, showing defects in the visceral endoderm. BHD heterozygous knockout (BHDd(/+)) mice appeared normal at birth but developed kidney cysts and solid tumors as they aged (median kidney-lesion-free survival = 23 months, median tumor-free survival = 25 months). As observed in human BHD kidney tumors, three different histologic types of kidney tumors developed in BHD(d/+) mice including oncocytic hybrid, oncocytoma, and clear cell with concomitant loss of heterozygosity (LOH), supporting a tumor suppressor function for BHD in the mouse. The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHD(d/+) mice. Interestingly, total AKT protein was elevated in kidney tumors compared to normal kidney tissue, but without increased levels of AKT mRNA, suggesting that AKT may be regulated by folliculin through post translational or post-transcriptional modification. Finally, BHD inactivation led to both mTORC1 and mTORC2 activation in kidney tumors from BHD(d/+) mice and human BHD patients. These data support a role for PI3K-AKT pathway activation in kidney tumor formation caused by loss of BHD and suggest that inhibitors of both mTORC1 and mTORC2 may be effective as potential therapeutic agents for BHD-associated kidney cancer.
BHD/FLCN肿瘤抑制基因的种系突变使患者易患错构瘤综合征（Birt-Hogg-Dubé，BHD）中的肾肿瘤。BHD编码卵泡抑素，这是一种功能未知的蛋白质，可能与能量和营养感知的AMPK-mTOR信号通路相互作用。为了阐明BHD在小鼠中的功能，我们构建了一个BHD基因敲除小鼠模型。BHD纯合缺失（BHD(d/d)）小鼠在E5.5-E6.5时出现早期胚胎致死，表现为脏内胚层缺陷。BHD杂合敲除（BHDd(/+)）小鼠出生时外观正常，但随着年龄增长会出现肾囊肿和实体瘤（中位无肾损伤生存期 = 23个月，中位无瘤生存期 = 25个月）。正如在人类BHD肾肿瘤中观察到的那样，BHD(d/+)小鼠出现了三种不同组织学类型的肾肿瘤，包括嗜酸细胞混合瘤、嗜酸细胞瘤和透明细胞癌，并伴有杂合性缺失（LOH），这支持了BHD在小鼠中的肿瘤抑制功能。PI3K-AKT通路在人类BHD肾肿瘤和BHD(d/+)小鼠的肾肿瘤中均被激活。有趣的是，与正常肾组织相比，肾肿瘤中总AKT蛋白升高，但AKT mRNA水平未升高，这表明AKT可能通过翻译后或转录后修饰受到卵泡抑素的调节。最后，BHD失活导致BHD(d/+)小鼠肾肿瘤和人类BHD患者肾肿瘤中的mTORC1和mTORC2均被激活。这些数据支持PI3K-AKT通路激活在BHD缺失导致的肾肿瘤形成中起作用，并表明mTORC1和mTORC2抑制剂可能作为BHD相关肾癌的潜在治疗药物有效。
