Abstract
The potential impact of Vav1 on human cancer was only recently acknowledged, as it is detected as a mutant or an overexpressed gene in various cancers, including lung cancer. Vav1, which is normally and exclusively expressed in the hematopoietic system functions as a specific GDP/GTP nucleotide exchange factor (GEF), strictly regulated by tyrosine phosphorylation. To investigate whether Vav1 plays a causative or facilitating role in-vivo in lung cancer development and to examine whether it co-operates with other oncogenes, such as mutant K-Ras, we generated novel mouse strains that express: Vav1 or K-RasG12D in type II pneumocytes, as well as a transgenic mouse line that expresses both Vav1 and K-RasG12D in these cells. Coexpression of Vav1 and K-RasG12D in the lungs dramatically increased malignant lung cancer lesions, and did so significantly faster than K-RasG12D alone, strongly suggesting that these two oncogenes synergize to enhance lung tumor development. Vav1 expression alone had no apparent effects on lung tumorigenesis. The increase in lung cancer in K-RasG12D/Vav1 mice was accompanied by an increase in B-cell, T-cells, and monocyte infiltration in the tumor microenvironment. Concomitantly, ERK phosphorylation was highly elevated in the lungs of K-RasG12 D/Vav1 mice. Also, several cytokines such as IL-4 and IL-13 which play a significant role in the immune system, were elevated in lungs of Vav1 and K-RasG12 D/Vav1 mice. Our findings emphasize the contribution of Vav1 to lung tumor development through its signaling properties.
Original language | American English |
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Article number | 110395 |
Journal | Cellular Signalling |
Volume | 97 |
DOIs | |
State | Published - Sep 2022 |
Bibliographical note
Funding Information:This work was partially supported by grants from the Israel Science Foundation : 333/13&654/18 ; the Israel Cancer Association ( ICA;07/20&2/21 ; supported by Ms. Y. Doron); The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research; and a donation from Vibeke Lichten.
Publisher Copyright:
© 2022 Elsevier Inc.
Keywords
- ERK
- K-Ras
- Lung Cancer
- Vav1