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Significance of NOTCH1 Expression in the Progression of Human Lung and Colorectal Cancers

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Abstract

Lung and colorectal cancers are the most common types of cancer characterized by a poor prognosis and a high mortality rate. Mutations in the genes encoding components of the main intra- and extracellular signaling pathways, in particular the NOTCH1 gene (Notch1, a member of the Notch family of receptors), play one of the key roles in progression of these malignancies. Notch signaling is involved in maintaining homeostasis of the intestinal epithelium and structural and functional lung elements. Therefore, it is not surprising that the constitutive activity and hyperactivity of Notch signaling due to somatic mutations in genes coding for the products directly involved into its activation, could lead to the progression of these cancer types. The aim of our study was to investigate how the NOTCH1 downregulation via RNA interference (RNAi) affects the phenotype, characteristics, and Notch-dependent signaling of human A549 lung and HCT116 colorectal carcinoma cells. Several small harpin RNAs (shRNAs) were selected using the bioinformatic analysis and tested for their ability to suppress the NOTCH1 expression. The most efficient one was used to produce the A549 and HCT116 cells with NOTCH1 knockdown. The obtained cell lines demonstrated decreased proliferation rates, reduced colony-forming capacity under adhesive conditions, and decreased migration activity in a Boyden chamber. The NOTCH1 knockdown also significantly decreased expression of some Notch signaling target genes potentially involved in the acquisition and maintenance of more invasive and malignant cell phenotype. In vivo experiments in immunodeficient athymic female Balb/c nu/nu mice confirmed the results obtained in vitro: the NOTCH1 inhibition decreased the growth rates of the subcutaneous xenografts formed by A549 and HCT116 tumor cells. Therefore, downregulation of the gene encoding the Notch1 receptor potentially reduces malignant characteristics of human lung and colorectal carcinoma cells.

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Abbreviations

GSI:

gamma-secretase inhibitor

RNAi:

RNA interference

qPCR:

quantitative PCR

shRNA:

small harpin RNA

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Funding

This work was supported by the Russian Science Foundation (project no. 20-15-00321).

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Authors and Affiliations

  1. Blokhin National Medical Research Center of Oncology, 115478, Moscow, Russia

    Maria V. Vasileva, Natalia V. Khromova, Boris P. Kopnin & Pavel B. Kopnin

  2. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992, Moscow, Russia

    Vera B. Dugina

Authors
  1. Maria V. Vasileva
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  2. Natalia V. Khromova
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  3. Boris P. Kopnin
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  4. Vera B. Dugina
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  5. Pavel B. Kopnin
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Contributions

M.V. analyzed the published data, carried out the experiments and wrote the article. N.K. carried out the experiments. B.K. contributed to the statistical analysis of the results. V.D. carried out the experiments. P.K. designed the study, carried out the experiments and wrote the article.

Corresponding author

Correspondence to Pavel B. Kopnin.

Ethics declarations

The authors declare no conflict of interest. The animal study protocol was approved by the Biomedical Ethics Committee of Blokhin National Medical Research Center of Oncology. The study was performed in accordance with all ethical standards for the animal treatment adopted by the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes.

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Vasileva, M.V., Khromova, N.V., Kopnin, B.P. et al. Significance of NOTCH1 Expression in the Progression of Human Lung and Colorectal Cancers. Biochemistry Moscow 87, 1199–1205 (2022). https://doi.org/10.1134/S0006297922100133

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  • DOI: https://doi.org/10.1134/S0006297922100133

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