ITIH5 induces a shift in TGF-β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death
ITIH5 induces a shift in TGF-β superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death
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DOI：
10.1002/mc.22742
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发表时间：
2018-02-01
影响因子：
4.6
通讯作者：
Dahl, Edgar
中科院分区：
文献类型：
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作者：
Rose, Michael;Meurer, Steffen K.;Dahl, Edgar
ITIH5在包括乳腺癌在内的多种肿瘤实体中被认为是一种新的肿瘤抑制因子。最近，ITIH5在胰腺癌中被进一步鉴定为转移抑制基因。在本研究中，我们旨在明确ITIH5对乳腺癌转移的影响。因此，使用TCGA门户和甲基化特异性PCR （MSP）评估乳腺癌转移中ITIH5启动子区域的DNA甲基化。我们发现ITIH5上游启动子区域特别负责ITIH5基因失活，预测患者的生存期缩短。值得注意的是，上游ITIH5启动子区域的甲基化与疾病进展相关，例如，在远处转移中大量发现。在体外，使用稳定过表达itih5的MDA-MB-231乳腺癌克隆分析细胞侵袭并鉴定新的itih5下游靶点。事实上，ITIH5的重新表达抑制了MDA-MB-231乳腺癌细胞的侵袭性生长，同时调节了包括内啡肽（ENG）在内的参与转移的基因的表达，内啡肽是一种辅助tgf - β受体，在原发性乳腺肿瘤中与ITIH5共表达。通过使用tgf - β 1和BMP-2进行tgf - β信号的体外刺激，我们发现ITIH5触发tgf - β超家族信号开关，导致Id1等靶标下调，已知其支持转移。此外，ITIH5仅在那些具有高ENG表达或ID1负调控的乳腺肿瘤中预测更长的总生存期（OS），这表明ITIH5-ENG轴对乳腺癌进展的临床和功能影响。因此，我们提供的证据表明，ITIH5可能代表一种新的tgf - β超家族信号调节剂，参与抑制乳腺癌转移。
ITIH5 has been proposed being a novel tumor suppressor in various tumor entities including breast cancer. Recently, ITIH5 was furthermore identified as metastasis suppressor gene in pancreatic carcinoma. In this study we aimed to specify the impact of ITIH5 on metastasis in breast cancer. Therefore, DNA methylation of ITIH5 promoter regions was assessed in breast cancer metastases using the TCGA portal and methylation-specific PCR (MSP). We reveal that the ITIH5 upstream promoter region is particularly responsible for ITIH5 gene inactivation predicting shorter survival of patients. Notably, methylation of this upstream ITIH5 promoter region was associated with disease progression, for example, abundantly found in distant metastases. In vitro, stably ITIH5-overexpressing MDA-MB-231 breast cancer clones were used to analyze cell invasion and to identify novel ITIH5-downstream targets. Indeed, ITIH5 re-expression suppresses invasive growth of MDA-MB-231 breast cancer cells while modulating expression of genes involved in metastasis including Endoglin (ENG), an accessory TGF-beta receptor, which was furthermore co-expressed with ITIH5 in primary breast tumors. By performing in vitro stimulation of TGF-beta signaling using TGF-beta 1 and BMP-2 we show that ITIH5 triggered a TGF-beta superfamily signaling switch contributing to downregulation of targets like Id1, known to endorse metastasis. Moreover, ITIH5 predicts longer overall survival (OS) only in those breast tumors that feature high ENG expression or inversely regulated ID1 suggesting a clinical and functional impact of an ITIH5-ENG axis for breast cancer progression. Hence, we provide evidence that ITIH5 may represent a novel modulator of TGF-beta superfamily signaling involved in suppressing breast cancer metastasis.