Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands

被引：25

作者：

Almazan-Moga, A. ^{[1
]}

Zarzosa, P. ^{[1
]}

Molist, C. ^{[1
]}

Velasco, P. ^{[1
]}

Pyczek, J. ^{[2
]}

Simon-Keller, K. ^{[3
]}

Giralt, I. ^{[1
]}

Vidal, I. ^{[1
]}

Navarro, N. ^{[1
]}

Segura, M. F. ^{[1
]}

Soriano, A. ^{[1
]}

Navarro, S. ^{[4
]}

Tirado, O. M. ^{[5
]}

Ferreres, J. C. ^{[6
]}

Santamaria, A. ^{[7
]}

Rota, R. ^{[8
]}

Hahn, H. ^{[2
]}

de Toledo, J. Sanchez ^{[1
,9
]}

Roma, J. ^{[1
]}

Gallego, S. ^{[1
,9
]}

机构：

[1] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Lab Translat Res Pediat Canc, Barcelona 08035, Spain

[2] Univ Goettingen, Inst Human Genet, D-37073 Gottingen, Germany

[3] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, D-68167 Mannheim, Germany

[4] Univ Valencia, Biomed Res Inst INCLIVA, Dept Pathol, Valencia 46010, Spain

[5] Inst Invest Biomed Bellvitge IDIBEL, CIBERONC, Sarcoma Res Grp, Lab Oncol Mol,Oncobell, Lhospitalet De Llobregat 08908, Spain

[6] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Pathol Dept, Barcelona 08035, Spain

[7] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Cell Cycle & Canc Lab,Biomed Res Unit Gynaecol, Barcelona 08035, Spain

[8] Osped Pediat Bambino Gesuu, IRCCS, Dept Oncohematol, I-00165 Rome, Italy

[9] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Pediat Oncol & Hematol Dept, Barcelona 08035, Spain

来源：

BRITISH JOURNAL OF CANCER | 2017年 / 117卷 / 09期

关键词：

Rhabdomyosarcoma; Hedgehog; vismodegib; UPR; TRIB3; sarcoma; cancer; UNFOLDED PROTEIN RESPONSE; BASAL-CELL CARCINOMA; SIGNALING PATHWAY; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; HEPATOCELLULAR-CARCINOMA; MESENCHYMAL TRANSITION; TUMOR-DEVELOPMENT; HUMAN HOMOLOG; GENE;

D O I：

10.1038/bjc.2017.305

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. Methods: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. Results: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. Conclusions: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

引用

页码：1314 / 1325

页数：12

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