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The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma

Oncogene volume 38, pages 60–72 (2019)Cite this article

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Abstract

Metastatic clear cell renal cell carcinoma (CCC) remains incurable despite advances in the development of anti-angiogenic targeted therapies and the emergence of immune checkpoint inhibitors. We have previously shown that the sonic hedgehog-Gli signaling pathway is oncogenic in CCC allowing us to identify the developmental Lim1 transcription factor as a Gli target and as a new oncogene in CCC regulating cell proliferation and apoptosis, and promoting tumor growth. In this previous study, preliminary in vitro results also suggested that Lim1 may be implicated in metastatic spread. Here we investigated the potential pro-metastatic role of Lim1 in advanced CCC (1) in vitro using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene either naturally or by gene transfer and (2) ex vivo in 30 CCC metastatic tissues, including lymph nodes, lung, skin, bone, and adrenal metastases, and (3) in vivo, using a metastatic model by intravenous injection of siRNA-transfected cells into Balb/c nude. Our in vitro results reveal that Lim1 knockdown time-dependently decreased CCC cell motility, migration, invasion, and clonogenicity by up to 50% regardless of their VHL status. Investigating the molecular machinery involved in these processes, we identified a large panel of Lim1 targets known to be involved in cell adhesion (paxillin and fibronectin), epithelial-mesenchymal transition (Twist1/2 and snail), invasion (MMP1/2/3/8/9), and metastatic progression (CXCR4, SDF-1, and ANG-1). Importantly, Lim1 was found constitutively expressed in all metastatic tissues. The H-score in metastatic tissues being significantly superior to the score in the corresponding primary tumor tissues (P value = 0.009). Furthermore, we showed that Lim1 silencing decreases pulmonary metastasis development in terms of number and size in the in vivo metastatic model of human CCC. Taken together, these experiments strengthen the potential therapeutic value of Lim1 targeting as a promising novel approach for treating metastatic human CCC.

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Acknowledgements

This study was sponsored by INSERM (recipient TM), the University of Strasbourg (recipient TM), and the Ligue Contre le Cancer (recipient TM). The authors thank Martine MUCKENSTURM, Fabienne REYMANN, and Angélique WERCK, from the Department of Pathology, University Hospital, Strasbourg, for their technical assistance in immunohistochemistry.

Author information

Author notes

  1. Sabrina Danilin

    Present address: Firalis, 68330, Huningue, France

  2. Valérian Dormoy

    Present address: INSERM UMR_S1250, Université de Reims Champagne-Ardenne (URCA), CHU Maison Blanche, 45 rue Cognacq-Jay, 51092, Reims, France

Authors and Affiliations

  1. INSERM UMR_S1113, Section of Cell Signalisation and Communication in Kidney and Prostate Cancer, INSERM and University of Strasbourg, School of Medicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67085, Strasbourg, France

    Imène Hamaidi, Catherine Coquard, Sabrina Danilin, Valérian Dormoy, Sylvie Rothhut, Mariette Barthelmebs & Thierry Massfelder

  2. School of Medicine, UROLEAD SAS, 67085, Strasbourg, France

    Claire Béraud

  3. UMR_S1260, Regenerative Nanomedicine laboratory, INSERM and University of Strasbourg, School of Medicine, FMTS, 67085, Strasbourg, France

    Nadia Benkirane-Jessel

  4. Department of Pathology, Hôpital de Strasbourg-Hautepierre, Hôpitaux Universitaires de Strasbourg, 67200, Strasbourg, France

    Véronique Lindner

  5. Department of Urology, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 67091, Strasbourg, France

    Hervé Lang

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Hamaidi, I., Coquard, C., Danilin, S. et al. The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma. Oncogene 38, 60–72 (2019). https://doi.org/10.1038/s41388-018-0413-y

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