WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma.
WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma.
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发育和癌症模型显示，Wnt/β-连环蛋白依赖的信号在胰腺中介导多种表型结果，这些结果受环境、激活时间和强度的影响。虽然通常认为Wnt/β-catenin信号失调具有致瘤性，但目前尚不清楚Wnt/β-catenin信号失调在多大程度上影响胰腺腺癌（PDAC）的肿瘤进展。在本研究中，Wnt/β-catenin活性在PDAC细胞系和原发肿瘤的光谱中被表征。基于报告和基因表达的分析显示，在PDAC细胞系和患者肿瘤中，Wnt/β-catenin转录活性存在广泛的异质性，以及对外源性Wnt配体刺激的不同反应。实验生成的胰腺特异性基因表达标志Wnt/β-catenin转录激活被用于在切除的早期PDAC肿瘤队列中分层通路激活（N=41）。在该队列中，较高的Wnt/β-catenin激活与淋巴管侵袭和更差的疾病特异性生存显著相关（中位生存时间20.3个月对43.9个月，log rank P=0.03）。Wnt/β-catenin活性在PDAC细胞系中通过WLS基因沉默和小分子抑制剂IWP-2显著抑制Wnt/β-catenin活性，这两种方法都能功能性地阻断Wnt配体的加工和分泌，从而支持Wnt配体在介导自分泌Wnt信号传导中的重要性。转录谱分析显示，WNT7B在具有高水平细胞自主Wnt/β-catenin活性的PDAC细胞系中表达升高。在AsPC-1和haff -2细胞系中进行的基因敲低研究证实了WNT7B介导的细胞自主Wnt/β-catenin激活，以及一种不依赖锚定的生长表型。我们的研究结果表明，WNT7B可以作为PDAC中Wnt/β-catenin活化差异的主要决定因素。破坏Wnt配体与其受体之间的相互作用可能是治疗性调节PDAC和其他癌症环境中Wnt/β-catenin信号的一种特别合适的方法，其中Wnt激活是由配体表达介导的，而不是由典型途径成员的突变介导的。
Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation. An experimentally-generated, pancreas-specific gene expression signature of Wnt/β-catenin transcriptional activation was used to stratify pathway activation across a cohort of resected, early stage PDAC tumors (N=41). In this cohort, higher Wnt/β-catenin activation was found to significantly correlate with lymphvascular invasion and worse disease specific survival (median survival time 20.3 versus 43.9 months, log rank P=0.03). Supporting the importance of Wnt ligand in mediating autocrine Wnt signaling, Wnt/β-catenin activity was significantly inhibited in PDAC cell lines by WLS gene silencing and the small molecule inhibitor IWP-2, both of which functionally block Wnt ligand processing and secretion. Transcriptional profiling revealed elevated expression of WNT7B occurred in PDAC cell lines with high levels of cell autonomous Wnt/β-catenin activity. Gene knockdown studies in AsPC-1 and HPAF-2 cell lines confirmed WNT7B mediated cell autonomous Wnt/β-catenin activation, as well as an anchorage-independent growth phenotype. Our findings indicate WNT7B can serve as a primary determinant of differential Wnt/β-catenin activation in PDAC. Disrupting the interaction between Wnt ligands and their receptors may be a particularly suitable approach for therapeutic modulation of Wnt/β-catenin signaling in PDAC and other cancer contexts where Wnt activation is mediated by ligand expression rather than mutations in canonical pathway members.
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DOI：
10.1038/jid.2008.445
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Chien AJ;Conrad WH;Moon RT
通讯作者：
Moon RT
DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
3
作者：
Chang JT;Gatza ML;Lucas JE;Barry WT;Vaughn P;Nevins JR
通讯作者：
Nevins JR
影响因子：
3.2
作者：
Gerdes, B;Ramaswamy, A;Bartsch, D
通讯作者：
Bartsch, D
影响因子：
3.7
作者：
Pasca di Magliano M;Biankin AV;Heiser PW;Cano DA;Gutierrez PJ;Deramaudt T;Segara D;Dawson AC;Kench JG;Henshall SM;Sutherland RL;Dlugosz A;Rustgi AK;Hebrok M
通讯作者：
Hebrok M