Related Experiment Video
Updated: Nov 19, 2025
Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
Published on: August 2, 2018
Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α
Hisanori Isomura1,2, Ayumu Taguchi2,3, Taisuke Kajino1,2
1Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Abstract:
We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.
Insights
Targeting the receptor tyrosine kinase-like orphan receptor 1 (ROR1) significantly inhibits lung adenocarcinoma growth in vivo. ROR1 ablation reduces tumor progression and improves survival by downregulating hypoxia-induced genes and HIF-1α.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is implicated in various cancers, including lung adenocarcinoma.
- ROR1 is a downstream target of the TTF-1/NKX2-1 oncogene, suggesting its role in lung cancer progression.
- The therapeutic potential of targeting ROR1 in vivo remains largely undetermined.
Purpose of the Study:
- To investigate the in vivo role of ROR1 in lung adenocarcinoma development and progression.
- To determine if targeting ROR1 can inhibit tumor growth and improve survival.
- To elucidate the molecular mechanisms by which ROR1 influences tumor microenvironment, specifically hypoxia.
Main Methods:
- Generation of genetically engineered mice with floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene.
- Assessment of tumor development, progression, malignant characteristics, and survival following Ror1 ablation.
- Gene set enrichment analysis to identify pathways affected by Ror1 ablation.
- In vitro knockdown of ROR1 in lung adenocarcinoma cell lines to evaluate its effect on HIF-1α expression under normoxia and hypoxia.
Main Results:
- Ror1 ablation in mice significantly retarded lung adenocarcinoma development and progression.
- Tumor-bearing mice with Ror1 ablation exhibited reduced malignant characteristics and significantly improved survival.
- Gene set enrichment analysis revealed significant downregulation of hypoxia-induced genes (HALLMARK_HYPOXIA) upon Ror1 ablation.
- ROR1 knockdown diminished HIF-1α expression under normoxia and impaired its induction in response to hypoxia in lung cancer cells.
Conclusions:
- ROR1 plays a critical role in the in vivo development and progression of lung adenocarcinoma.
- ROR1 is identified as a novel regulator of HIF-1α, influencing the hypoxic tumor microenvironment.
- Targeting ROR1 represents a promising therapeutic strategy for lung cancer and other solid tumors with hypoxic microenvironments.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:23Abnormal Proliferation
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:03Rous Sarcoma Virus (RSV) and Cancer
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...
02:38The Ras Gene
Ras is a...