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The Lim1 oncogene as a new therapeutic target for metastatic human renal cell carcinoma
- Source :
- Oncogene, Oncogene, Nature Publishing Group, 2019, 38 (1), pp.60-72. ⟨10.1038/s41388-018-0413-y⟩, Oncogene, 2019, 38 (1), pp.60-72. ⟨10.1038/s41388-018-0413-y⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- International audience; 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Lung Neoplasms
[SDV]Life Sciences [q-bio]
CXCR4
[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology
Metastasis
0302 clinical medicine
Invasion
Cell Movement
Molecular Targeted Therapy
RNA, Small Interfering
mouse xenograft model
ComputingMilieux_MISCELLANEOUS
Primary tumor
Kidney Neoplasms
3. Good health
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Von Hippel-Lindau Tumor Suppressor Protein
030220 oncology & carcinogenesis
Gene Knockdown Techniques
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
RNA Interference
Lim1
Signal Transduction
Epithelial-Mesenchymal Transition
Tumor suppressor gene
human renal cell carcinoma
LIM-Homeodomain Proteins
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
In vivo
Cell Line, Tumor
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Genetics
medicine
Gene silencing
Humans
Neoplasm Invasiveness
Molecular Biology
Carcinoma, Renal Cell
Oncogene
Cell growth
Oncogenes
medicine.disease
[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology
Clear cell renal cell carcinoma
030104 developmental biology
Tumorigenesis
Cancer research
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 09509232 and 14765594
- Database :
- OpenAIRE
- Journal :
- Oncogene, Oncogene, Nature Publishing Group, 2019, 38 (1), pp.60-72. ⟨10.1038/s41388-018-0413-y⟩, Oncogene, 2019, 38 (1), pp.60-72. ⟨10.1038/s41388-018-0413-y⟩
- Accession number :
- edsair.doi.dedup.....8a883a794d857619e87d7da6af8bfaf6