Promotion of epithelial hyperplasia by interleukin-8-CXCR axis in human prostate.
Promotion of epithelial hyperplasia by interleukin-8-CXCR axis in human prostate.
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DOI：
10.1002/pros.24026
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Lokeshwar BL
中科院分区：
文献类型：
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作者：
Smith DK;Hasanali SL;Wang J;Kallifatidis G;Morera DS;Jordan AR;Terris MK;Klaassen Z;Bollag R;Lokeshwar VB;Lokeshwar BL
良性前列腺增生（BPH）的临床表现与前列腺移行区的炎症微环境以及上皮细胞和基质细胞的增殖有因果关系。 CXC 趋化因子白细胞介素 8 (IL-8) 会导致炎症。我们评估了临床标本、原代培养物和前列腺谱系细胞系中炎症细胞因子的表达。我们研究了 IL-8 是否通过其受体系统（IL-8 轴）促进 BPH。在正常前列腺 (NP; n = 7) 和 BPH (n = 21)、尿液 (n = 24) 样本、原代培养物、前列腺谱系上皮细胞系 (NHPrE1、BHPrE1、BPH-1) 和正常前列腺细胞 (RWPE-1) 中测量趋化因子的信使 RNA 和蛋白表达，包括 IL-8 轴的成分。通过 CRISPR/Cas9 基因编辑评估了 IL-8 轴在前列腺上皮细胞生长中的功能作用。评估了齐墩果酸 (OA) 和熊果酸 (UA) 两种天然化合物的组合对 IL-8 轴表达和上皮细胞生长的影响。在我们分析的 19 种炎症趋化因子和趋化因子受体中，与 NP 组织相比，BPH 组织中 IL-8 及其受体（CXCR1、CXCR2）以及 CXCR7（CXCL12 受体）的水平升高 5 至 25 倍（P ≤ .001）。 BPH 患者的尿液 IL-8 水平升高了三到六倍，但在有下尿路症状的无症状男性和女性中则没有升高 (P ≤ .004)。 IL-8轴成分的表达仅限于正常组织和BPH组织中的前列腺管腔上皮细胞。然而，与 RWPE-1、NHPrE1 和 BHPrE1 细胞相比，这些成分在 BPH-1 和原代外植体培养物中升高。 CXCR7 的敲除使 IL-8 和 CXCR1 的表达降低了 4 至 10 倍，并导致 BPH-1 细胞的生长抑制大于或等于 50%。低剂量 OA + UA 组合可协同抑制 BPH-1 和 BPH 原代培养物的生长。在联合用药中，UA 和 OA 的药物减少指数分别为 16.4 和 7852，表明单独使用显着降低的 UA 或 OA 剂量时，该联合用药可有效抑制 BPH-1 生长。 IL-8轴是BPH发病机制的启动子。低剂量 OA + UA 组合通过诱导 BPH 上皮细胞自噬和减少 IL-8 轴表达来抑制 BPH 细胞生长。
The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.
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DOI：
10.1158/1078-0432.ccr-08-0738
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Caruso DJ;Carmack AJ;Lokeshwar VB;Duncan RC;Soloway MS;Lokeshwar BL
通讯作者：
Lokeshwar BL
影响因子：
5.2
作者：
Caunii A;Oprean C;Cristea M;Ivan A;Danciu C;Tatu C;Paunescu V;Marti D;Tzanakakis G;Spandidos DA;Tsatsakis A;Susan R;Soica C;Avram S;Dehelean C
通讯作者：
Dehelean C
DOI：
10.3390/molecules22111915
发表时间：
2017-11-13
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Ayeleso TB;Matumba MG;Mukwevho E
通讯作者：
Mukwevho E
影响因子：
14.8
作者：
Drost J;Karthaus WR;Gao D;Driehuis E;Sawyers CL;Chen Y;Clevers H
通讯作者：
Clevers H
DOI：
10.4196/kjpp.2017.21.6.651
发表时间：
2017-11
期刊：
The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology
影响因子：
--
作者：
Bang HS;Seo DY;Chung YM;Kim DH;Lee SJ;Lee SR;Kwak HB;Kim TN;Kim M;Oh KM;Son YJ;Kim S;Han J
通讯作者：
Han J