Theranostics 2021; 11(8):3661-3675. doi:10.7150/thno.53176

Research Paper

Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma

Wei-Chung Cheng1,2,3, Chun-Yu Chang4, Chia-Chien Lo4, Chih-Ying Hsieh4, Ting-Ting Kuo4, Guan-Chin Tseng5, Sze-Ching Wong4, Shu-Fen Chiang6, Kevin Chih-Yang Huang7,8, Liang-Chuan Lai9, Tzu-Pin Lu10, K.S. Clifford Chao11,12✉, Yuh-Pyng Sher2,4,13,14✉

1. Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taiwan.
2. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
3. Research Center for Cancer Biology, China Medical University Hospital, Taichung 404, Taiwan.
4. Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan.
5. Department of Anatomic Pathology, Nantou Hospital of the Ministry of Health and Welfare, Nantou 540, Taiwan.
6. Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 420, Taiwan.
7. Translation Research Core, China Medical University Hospital, Taichung 404, Taiwan.
8. Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan.
9. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
10. Department of Public Health, National Taiwan University, Taipei 100, Taiwan.
11. Cancer Center, China Medical University Hospital, Taichung 404, Taiwan.
12. School of Medicine, China Medical University, Taichung 404, Taiwan.
13. Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan.
14. Research Center for Chinese Herbal Medicine, China Medical University, Taichung 404, Taiwan.

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Citation:
Cheng WC, Chang CY, Lo CC, Hsieh CY, Kuo TT, Tseng GC, Wong SC, Chiang SF, Huang KCY, Lai LC, Lu TP, Chao KSC, Sher YP. Identification of theranostic factors for patients developing metastasis after surgery for early-stage lung adenocarcinoma. Theranostics 2021; 11(8):3661-3675. doi:10.7150/thno.53176. Available from https://www.thno.org/v11p3661.htm

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Abstract

Rationale: Lung adenocarcinoma (LUAD) is an aggressive disease with high propensity of metastasis. Among patients with early-stage disease, more than 30% of them may relapse or develop metastasis. There is an unmet medical need to stratify patients with early-stage LUAD according to their risk of relapse/metastasis to guide preventive or therapeutic approaches. In this study, we identified 4 genes that can serve both therapeutic and diagnostic (theranostic) purposes.

Methods: Three independent datasets (GEO, TCGA, and KMPlotter) were used to evaluate gene expression profile of patients with LUAD by unbiased screening approach. Upon significant genes uncovered, functional enrichment analysis was carried out. The predictive power of their expression on patient prognosis were evaluated. Once confirmed their theranostic roles by integrated bioinformatics, we further conducted in vitro and in vivo validation.

Results: We found that four genes (ADAM9, MTHFD2, RRM2, and SLC2A1) were associated with poor patient outcomes with an increased hazard ratio in LUAD. Knockdown of them, both separately and simultaneously, suppressed lung cancer cell proliferation and migration ability in vitro and prolonged survival time in metastatic tumor mouse models. Moreover, these four biomarkers were found to be overexpressed in tumor tissues from LUAD patients, and the total immunohistochemical staining scores correlated with poor prognosis.

Conclusions: These results suggest that these four identified genes could be theranostic biomarkers for stratifying high-risk patients who develop relapse/metastasis in early-stage LUAD. Developing therapeutic approaches for the four biomarkers may benefit early-stage LUAD patients after surgery.

Keywords: Lung adenocarcinoma, prognostic biomarkers, early-stage lung adenocarcinoma.