TY - JOUR
T1 - Identification of targetable kinases in idiopathic pulmonary fibrosis
AU - Higo, Hisao
AU - Ohashi, Kadoaki
AU - Tomida, Shuta
AU - Okawa, Sachi
AU - Yamamoto, Hiromasa
AU - Sugimoto, Seiichiro
AU - Senoo, Satoru
AU - Makimoto, Go
AU - Ninomiya, Kiichiro
AU - Nakasuka, Takamasa
AU - Nishii, Kazuya
AU - Taniguchi, Akihiko
AU - Kubo, Toshio
AU - Ichihara, Eiki
AU - Hotta, Katsuyuki
AU - Miyahara, Nobuaki
AU - Maeda, Yoshinobu
AU - Toyooka, Shinichi
AU - Kiura, Katsuyuki
N1 - Funding Information:
This research received a specific grant from JSPS Grants-in-Aid for Scientific Research [Grant-in-Aid for Challenging Exploratory Research: KAKEN 16K15458 to K. Ohashi, T. Kubo and K. Kiura], and JSPS Grants-in-Aid for Scientific Research [Grant-in-Aid for Young Scientists (B): KAKEN 18K15925 to T. Kubo].
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Background: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). Methods: Thirteen samples from five patients with IPF (Cases 1–5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). Results: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. Conclusions: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.
AB - Background: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). Methods: Thirteen samples from five patients with IPF (Cases 1–5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). Results: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. Conclusions: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.
KW - Idiopathic pulmonary fibrosis
KW - Molecular therapeutic target
KW - Personalized therapy
KW - RNA sequencing
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U2 - 10.1186/s12931-022-01940-y
DO - 10.1186/s12931-022-01940-y
M3 - Article
C2 - 35130915
AN - SCOPUS:85124319097
SN - 1465-9921
VL - 23
JO - Respiratory Research
JF - Respiratory Research
IS - 1
M1 - 20
ER -
