The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors.
The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors.
复制标题
高迁移率组 A1 (HMGA1) 基因在人类子宫浆液性癌和癌肉瘤中高度过表达，并在肿瘤的子集中驱动基质金属蛋白酶-2 (MMP-2)。
DOI：
10.1016/j.ygyno.2016.03.020
复制
发表时间：
2016-06
影响因子：
4.7
通讯作者：
Resar LMS
中科院分区：
文献类型：
--
作者：
Hillion J;Roy S;Heydarian M;Cope L;Xian L;Koo M;Luo LZ;Kellyn K;Ronnett BM;Huso T;Armstrong D;Reddy K;Huso DL;Resar LMS
虽然子宫癌是全球女性癌症死亡的第四大常见原因，但肿瘤进展的分子基础仍然知之甚少。高迁移率族A1（HMGA 1）基因在侵袭性癌症中过表达，高水平预示着各种肿瘤的不良后果。我们以前报道过Hmga 1转基因小鼠发生子宫肿瘤，并完全转移。由于HMGA 1通过诱导基质金属蛋白酶（MMP）和其他参与侵袭的基因来驱动肿瘤进展，我们探索了子宫癌中的HMGA 1-MMP-2通路。为了研究由HMGA 1驱动的子宫肿瘤中的MMP-2，我们使用了小鼠模型的遗传方法。接下来，我们评估了HMGA 1和MMP-2在原发性人类子宫肿瘤中的表达，包括低级别癌（子宫内膜类腺瘤）和更具侵袭性的肿瘤（子宫内膜浆液性癌，子宫癌肉瘤/恶性中胚层混合瘤）。在这里，我们报告的第一次，子宫肿瘤的生长受损Hmga 1a转基因小鼠杂交到Mmp-2缺陷的背景。在人类肿瘤中，我们发现HMGA 1在侵袭性癌细胞瘤和浆液性癌中最高，在更惰性的类肉瘤中水平较低。此外，HMGA 1和MMP-2呈正相关，但仅在一个亚组的癌性肉瘤。HMGA 1在人癌肉瘤细胞中也占据MMP-2启动子。总之，我们的研究确定了一种新的HMGA 1-MMP-2通路参与了一个子集的人癌细胞瘤和肿瘤进展的小鼠模型。我们的工作还表明，靶向HMGA 1可能是更侵袭性子宫癌的有效辅助治疗，并为进一步的临床前研究提供了令人信服的数据。
Although uterine cancer is the fourth most common cause for cancer death in women worldwide, the molecular underpinnings of tumor progression remain poorly understood. The High Mobility Group A1 (HMGA1) gene is overexpressed in aggressive cancers and high levels portend adverse outcomes in diverse tumors. We previously reported that Hmga1 transgenic mice develop uterine tumors with complete penetrance. Because HMGA1 drives tumor progression by inducing matrix metalloproteinase (MMP) and other genes involved in invasion, we explored the HMGA1-MMP-2 pathway in uterine cancer. To investigate MMP-2 in uterine tumors driven by HMGA1, we used a genetic approach with mouse models. Next, we assessed HMGA1 and MMP-2 expression in primary human uterine tumors, including low-grade carcinomas (endometrial endometrioid) and more aggressive tumors (endometrial serous carcinomas, uterine carcinosarcomas/malignant mesodermal mixed tumors). Here, we report for the first time that uterine tumor growth is impaired in Hmga1a transgenic mice crossed on to an Mmp-2 deficient background. In human tumors, we discovered that HMGA1 is highest in aggressive carcinosarcomas and serous carcinomas, with lower levels in the more indolent endometrioid carcinomas. Moreover, HMGA1 and MMP-2 were positively correlated, but only in a subset of carcinosarcomas. HMGA1 also occupies the MMP-2 promoter in human carcinosarcoma cells. Together, our studies define a novel HMGA1-MMP-2 pathway involved in a subset of human carcinosarcomas and tumor progression in murine models. Our work also suggests that targeting HMGA1 could be effective adjuvant therapy for more aggressive uterine cancers and provides compelling data for further preclinical studies.
登录
查看更多内容
影响因子：
11.2
作者：
Resar LM
通讯作者：
Resar LM
影响因子：
2.6
作者：
Di Cello, Francescopaolo;Dhara, Surajit;Resar, Linda
通讯作者：
Resar, Linda
影响因子：
4.9
作者：
Chung, Amy S.;Waldeck, Heather;Kao, Weiyuan John
通讯作者：
Kao, Weiyuan John
影响因子：
11.2
作者：
Liau, Siong-Seng;Jazag, Amarsanaa;Whang, Edward E.
通讯作者：
Whang, Edward E.
DOI：
10.1016/j.pan.2012.05.005
发表时间：
2012-07
期刊：
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
影响因子：
--
作者：
Hillion J;Smail SS;Di Cello F;Belton A;Shah SN;Huso T;Schuldenfrei A;Nelson DM;Cope L;Campbell N;Karikari C;Aderinto A;Maitra A;Huso DL;Resar LM
通讯作者：
Resar LM