Abstract
Purpose
Histologic classification of invasive lung adenocarcinomas by predominant subtype has prognostic value. Papillary predominant adenocarcinoma (PPA) reportedly shows poorer prognosis than lepidic predominant adenocarcinoma (LPA); however, biological differences between PPA and LPA are unclear. The purpose of this study was to clarify biological differences between PPA and LPA.
Methods
Clinicopathological characteristics of invasive 62 PPAs and 117 LPAs smaller than 30 mm were investigated. Furthermore, we compared immunochemical staining scores of 9 molecular markers (E-cadherin, S100A4, fibronectin, integrinβ1, ezrin, GLUT1, ALDH1, SOX2 and Nanog) between PPA and LPA. We performed Western blot analysis using ezrin shRNA-knockdown lung adenocarcinoma cell lines to examine whether molecules that are highly expressed in PPA, such as ezrin, affect pAkt. Finally, we performed immunochemical staining to compare pAkt expression level in PPA and LPA.
Results
Lymphovascular and pleural invasion and lymph node metastasis were significantly more often detected in PPA than in LPA (lymphatic permeation: 31 vs 3 %, vascular invasion: 35 vs 3 %, pleural invasion: 29 vs 5 %, lymph node metastasis: 18 vs 1 %; all P < 0.01). Immunohistochemical (IHC) study revealed that expression score of ezrin was significantly higher in PPA than in LPA (38.3 vs 15.0; P < 0.01). The level of pAkt decreased in shEzrin-induced PC-9 and A549 cancer cells. Moreover, the IHC staining score of pAkt was significantly higher in PPA than in LPA (13.3 vs 0.0; P < 0.01).
Conclusions
Our results show that the activation of the ezrin–pAkt signaling axis is associated with the more aggressive clinicopathological features of PPA compared with LPA.
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Abbreviations
- ALDH1:
-
Aldehyde dehydrogenase-1
- EGFR:
-
Epidermal growth factor receptor
- EMT:
-
Epithelial–mesenchymal transition
- GLUT1:
-
Glucose transporter-1
- IHC:
-
Immunohistochemical
- LPA:
-
Lepidic predominant adenocarcinoma
- mTOR:
-
Mammalian target of rapamycin
- pAkt:
-
Phospho-Akt
- PI3K:
-
Phosphoinositide 3-kinase
- PPA:
-
Papillary predominant adenocarcinoma
- RNA:
-
Ribo nucleic acid
- shRNA:
-
Short hairpin RNA
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Acknowledgments
This work was supported by the National Cancer Center Research and Development Fund (23-A-16). We are grateful to Ms. Yuka Nakamura for her technical support.
Author contribution
KH, JY and GI conceived the study. KH, GI, HU and HH carried out the experiments. KH and GI analyzed the data. KH, JY and GI were involved in writing the paper. All authors had final approval of the manuscript.
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The authors have no conflict of interests to disclose.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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432_2016_2154_MOESM2_ESM.docx
Supplementary material 2 Figure S2: IHC staining for GLUT1 of LPA and PPA. Upper panel: LPA cancer cells show negative staining for GLUT1, while PPA cancer cells show positive staining for GLUT1 in both periphery and center of the tumor; lower panel: summary of GLUT1 staining scores for LPA and PPA (DOCX 857 kb)
432_2016_2154_MOESM3_ESM.docx
Supplementary material 3 Figure S3: Correlation between ezrin and pAkt expressions in each cases. Ezrin and pAkt expressions in each case tend to have positive correlation by using Spearman’s rank correlation coefficients (DOCX 94 kb)
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Hata, K., Yoshida, J., Udagawa, H. et al. The difference in Ezrin–pAkt signaling axis between lepidic and papillary predominant invasive adenocarcinomas of the lung. J Cancer Res Clin Oncol 142, 1421–1430 (2016). https://doi.org/10.1007/s00432-016-2154-z
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DOI: https://doi.org/10.1007/s00432-016-2154-z