Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.
Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.
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DOI：
10.3390/cancers12123640
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发表时间：
2020-12-04
期刊：
影响因子：
5.2
通讯作者：
Kopchick JJ
中科院分区：
文献类型：
--
作者：
Qian Y;Basu R;Mathes SC;Arnett NA;Duran-Ortiz S;Funk KR;Brittain AL;Kulkarni P;Terry JC;Davis E;Singerman JT;Henry BE;List EO;Berryman DE;Kopchick JJ
生长激素(GH)作用与GH受体(GHR)过度表达的几种实体瘤的进展和治疗耐药密切相关。本研究的目的是利用体外和体内模型研究生长激素及其下游效应胰岛素样生长因子-1(IGF-1)对黑色素瘤的影响。通过分子和细胞水平的分析，我们证实了循环GH升高在上调治疗耐药和恶性肿瘤的关键机制中不依赖于IGF-1的作用。我们发现GH通过上调多药外排泵和EMT转录因子，以IGF-1依赖和独立的方式上调黑色素瘤耐药和转移的关键机制。我们的研究表明，生长激素作用使黑色素瘤具有内在的耐药性表型--这是生长激素的一个临床关键特性，可在其他表达GHR的人类癌症中得到验证。生长激素(GH)及其受体(GHR)广泛表达于包括黑色素瘤在内的多种恶性肿瘤中。然而，生长激素/胰岛素样生长因子(GH/IGF)在体内对黑色素瘤的作用尚未阐明。在这里，我们评估了生长激素对体外培养的小鼠黑色素瘤B16-F10和人黑色素瘤SK-Mel-30细胞的物理和分子效应。然后，我们在两个不同GH/IGF水平的小鼠系中用同基因B16-F10肿瘤证实了这些观察结果：牛GH转基因小鼠(BGH；高GH，高IGF-1)和GHR基因缺失或敲除小鼠(GHRKO；高GH，低IGF-1)。在体外，GH治疗促进了小鼠和人黑色素瘤细胞的生长、药物滞留和细胞侵袭。虽然BGH和GHRKO小鼠体内的肿瘤大小没有受到影响，但多个药物外排泵被上调。这种固有的治疗抵抗能力似乎是生长激素依赖性的。此外，上皮向间充质转化(EMT)基因转录标记物在体内显著上调，支持我们目前和最近的体外观察。这些不同GH/IGF作用的同基因小鼠黑色素瘤模型在筛选降低GH/IGF-1作用的治疗方案中是有价值的工具。
Growth hormone (GH) action is strongly implicated in the progression and therapy resistance in several types of solid tumors which overexpress the GH receptor (GHR). The aim of our study was to characterize the effects of GH and its downstream effector insulin-like growth factor 1 (IGF-1) on melanoma using in vitro and in vivo models. We confirmed an IGF-1-independent role of elevated circulating GH in upregulating key mechanisms of therapy resistance and malignancy with analyses conducted at the molecular and cellular level. We identified that GH upregulates key mechanisms of therapy resistance and metastases in melanoma tumors in an IGF-1 dependent and independent manner by upregulating multidrug efflux pumps and EMT transcription factors. Our study reveals that GH action renders an intrinsic drug resistance phenotype to the melanoma tumors—a clinically crucial property of GH verifiable in other human cancers with GHR expression. Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.
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影响因子：
--
作者：
Basu R;Wu S;Kopchick JJ
通讯作者：
Kopchick JJ
影响因子：
11.2
作者：
Alonso, Soledad R.;Tracey, Lorraine;Rodriguez-Peralto, Jose L.
通讯作者：
Rodriguez-Peralto, Jose L.
自分泌人类生长激素通过 STAT3 依赖性抑制 CLAUDIN-1 表达促进肝细胞癌细胞的侵袭性和癌症干细胞样行为
影响因子：
5.6
作者：
Chen, Yi-Jun;You, Ming-Liang;Lobie, Peter E.
通讯作者：
Lobie, Peter E.
DOI：
10.20945/2359-3997000000186
发表时间：
2019-11-01
期刊：
Archives of Endocrinology and Metabolism
影响因子：
--
作者：
Chesnokova, Vera;Melmed, Shlomo
通讯作者：
Melmed, Shlomo
DOI：
10.1016/j.hoc.2012.01.004
发表时间：
2012-06
期刊：
Hematology/oncology clinics of North America
影响因子：
--
作者：
Arnaldez FI;Helman LJ
通讯作者：
Helman LJ