An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
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DOI：
10.1158/0008-5472.can-10-3072
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发表时间：
2011-06-01
期刊：
影响因子：
11.2
通讯作者：
Berman DM
中科院分区：
文献类型：
--
作者：
Ling S;Chang X;Schultz L;Lee TK;Chaux A;Marchionni L;Netto GJ;Sidransky D;Berman DM
与许多癌症一样，尿路上皮癌（UroCa）与慢性损伤有关。更好地了解这种关联可以为预防和治疗这种疾病的改进策略提供信息。我们研究了转录调控SRY相关HMG盒9（Sox 9）在尿路上皮发育、损伤修复和癌症中的表达、调节和功能。在小鼠膀胱中，Sox 9水平在产前尿路上皮发育期间很高，出生后随着成熟而减少。在成人尿路上皮细胞中，Sox 9是静止的，但被各种损伤迅速诱导，包括暴露于致癌物质环磷酰胺，过氧化氢培养和渗透压。细胞外信号调节激酶1/2（ERK 1/2）的激活是Sox 9诱导尿路上皮损伤所必需的，并且是由几种表皮生长因子受体（Egfr）配体激活引起的，这些配体由损伤显著诱导。在UroCa细胞系中，SOX 9的表达是组成性上调的，并且可以被EGFR或ERK 1/2阻断剂抑制。基因敲除证实了SOX 9在细胞迁移和侵袭中的作用。因此，与非侵袭性癌症（n=56）或良性邻近尿路上皮（n=49）相比，在侵袭性人UroCa组织样品（n=84）中优先诱导S 0X 9蛋白水平。这些结果确定了一个新的，潜在的致癌信号轴连接尿路上皮损伤UroCa。通过多种药理学方法抑制该轴是可行的，并且可能具有临床实用性。
Like many carcinomas, urothelial carcinoma (UroCa) is associated with chronic injury. A better understanding of this association could inform improved strategies for preventing and treating this disease. We investigated the expression, regulation, and function of the transcriptional regulator SRY-related HMG box 9 (Sox9) in urothelial development, injury repair, and cancer. In mouse bladders, Sox9 levels were high during periods of prenatal urothelial development and diminished with maturation after birth. In adult urothelial cells, Sox9 was quiescent but was rapidly induced by a variety of injuries, including exposure to the carcinogen cyclophosphamide, culture with hydrogen peroxide, and osmotic stress. Activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was required for Sox9 induction in urothelial injury and resulted from activation of the epidermal growth factor receptor (Egfr) by several Egfr ligands that were dramatically induced by injury. In UroCa cell lines, SOX9 expression was constitutively upregulated and could be suppressed by EGFR or ERK1/2 blockade. Gene knockdown demonstrated a role for SOX9 in cell migration and invasion. Accordingly, SOX9 protein levels were preferentially induced in invasive human UroCa tissue samples (n=84) compared to noninvasive cancers (n=56) or benign adjacent urothelium (n=49). These results identify a novel, potentially oncogenic signaling axis linking urothelial injury to UroCa. Inhibiting this axis is feasible through a variety of pharmacologic approaches and may have clinical utility.