Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.
Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.
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DOI：
10.1186/s12935-022-02818-1
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发表时间：
2022-12-29
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
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透明质酸（HA）促进癌症转移;然而，目前批准的治疗不靶向HA。转移性肾癌（mRCC）是一种无法治愈的疾病。索拉非尼（SF）是一种中等有效的mRCC抗血管生成药物。虽然只有内皮细胞表达已知的SF靶点，但SF在高于药理学剂量（5 μM）的浓度下对RCC细胞具有细胞毒性。使用患者队列、mRCC模型和SF与4-甲基伞形酮（MU）的组合，我们在RCC细胞中发现了SF靶标并将其靶向用于治疗。我们分析了RCC细胞和临床（n = 129）、TCGA-KIRC（n = 542）和TCGA-KIRP（n = 291）队列中HA合酶（HAS 1、HAS 2、HAS 3）的表达。我们评估了SF和SF + MU组合在RCC细胞、HAS 3转染子、内皮-RCC共培养物和异种移植物中的功效。肾细胞癌细胞HAS 3表达增加。在临床和TCGA-KIRC/TCGA-KIRP队列中，较高的HAS 3水平预测转移和较短的生存期。在> 10 μM剂量下，SF抑制HAS 3/HA合成和RCC细胞生长。然而，在≤ 5 μM剂量下，SF与MU组合抑制HAS 3/HA合成、RCC细胞和内皮-RCC共培养物的生长，并诱导细胞凋亡。该组合抑制运动/侵袭和HA信号传导相关的侵袭特征。我们先前表明，MU抑制RCC细胞中的SF失活。虽然HAS 3敲低转染子对SF敏感，但异位HAS 3表达诱导对组合的抗性。在RCC模型中，该组合抑制肿瘤生长和转移，毒性很小;然而，异位表达HAS 3的肿瘤具有抗性。HAS 3是RCC细胞中SF的第一个已知靶标。与MU（人体等效剂量，0.6-1.1 g/天）联合使用时，SF靶向HAS 3并有效消除mRCC。在线版本包含补充材料，可通过10.1186/s12935-022-02818-1获得。
Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6–1.1-g/day), SF targets HAS3 and effectively abrogates mRCC. The online version contains supplementary material available at 10.1186/s12935-022-02818-1.
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影响因子：
5.5
作者：
Hassn Mesrati M;Syafruddin SE;Mohtar MA;Syahir A
通讯作者：
Syahir A
影响因子：
15.9
作者：
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通讯作者：
Kaelin, William G., Jr.
影响因子：
6
作者：
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通讯作者：
Simpson, Melanie A.
DOI：
10.1016/j.bbrc.2012.05.147
发表时间：
2012-07-06
影响因子：
3.1
作者：
Kawazoe, Hisashi;Bilim, Vladimir N.;Tomita, Yoshihiko
通讯作者：
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影响因子：
7.3
作者：
Jordan AR;Racine RR;Hennig MJ;Lokeshwar VB
通讯作者：
Lokeshwar VB