Lung Tumorigenesis Alters the Expression of Slit2-exon15 Splicing Variants in Tumor Microenvironment

• Main Authors: Ming-Fang Wu, Cheng-Yen Chuang, Pinpin Lin, Wei-Ting Chen, Shang-Er Su, Chen-Yi Liao, Ming-Shiou Jan, Jinghua Tsai Chang
• Format: Article
• Language: English
• Published: MDPI AG 2019-02-01
• Series: Cancers
• Subjects: Slit2 splicing variants; lung cancer; pneumothorax; tumor microenvironment; kRas^G12D; LPS treatment; inflammation
• Online Access: https://www.mdpi.com/2072-6694/11/2/166

Slit2 expression is downregulated in various cancers, including lung cancer. We identified two Slit2 splicing variants at exon15—Slit2-WT and Slit2-ΔE15. In the RT-PCR analyses, the Slit2-WT isoform was predominantly expressed in all the lung cancer specimens and in their normal lung counterparts, whereas Slit2-ΔE15 was equivalently or predominantly expressed in 41% of the pneumothorax specimens. A kRas^G12D transgenic mice system was used to study the effects of tumorigenesis on the expressions of the Slit2-exon15 isoforms. The results revealed that a kRas^G12D-induced lung tumor increased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. However, the lung tumors generated via a tail vein injection of lung cancer cells decreased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. Interestingly, the lipopolysaccharide (LPS)-induced lung inflammation also decreased the Slit2-WT/Slit2-ΔE15 ratio. Since Slit2 functions as an anti-inflammatory factor, the expression of Slit2 increases in kRas^G12D lungs, which indicates that Slit2 suppresses immunity during tumorigenesis. However, an injection of lung cancer cells via the tail vein and the LPS-induced lung inflammation both decreased the Slit2 expression. The increased Slit2 in the tumor microenvironment was mostly Slit2-WT, which lacks growth inhibitory activity. Thus, the results of our study suggested that the upregulation of Slit2-WT, but not Slit2-ΔE15, in a cancer microenvironment is an important factor in suppressing immunity while not interfering with cancer growth.