The Prognostic Value of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma

Wangyang Meng; Han Xiao; Rong Zhao; Dong Li; Kuo Li; Yunchong Meng; Jiaping Chen; Yangwei Wang; Yongde Liao

doi:10.3389/fonc.2021.608239

The Prognostic Value of Bone Morphogenetic Proteins and Their Receptors in Lung Adenocarcinoma

Front Oncol. 2021 Oct 22:11:608239. doi: 10.3389/fonc.2021.608239. eCollection 2021.

Authors

Wangyang Meng¹, Han Xiao¹, Rong Zhao¹, Dong Li², Kuo Li¹, Yunchong Meng¹, Jiaping Chen¹, Yangwei Wang¹, Yongde Liao¹

Affiliations

¹ Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Dermatology and Sexology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Background: Bone morphogenetic proteins (BMPs) regulate tumor progression via binding to their receptors (BMPRs). However, the expression and clinical significance of BMPs/BMPRs in lung adenocarcinoma remain unclear due to a lack of systematic studies.

Methods: This study screened differentially expressed BMPs/BMPRs (deBMPs/BMPRs) in a training dataset combining TCGA-LUAD and GTEx-LUNG and verified them in four GEO datasets. Their prognostic value was evaluated via univariate and multivariate Cox regression analyses. LASSO was performed to construct an initial risk model. Subsequently, after weighted gene co-expression network analysis (WGCNA), differential expression analysis, and univariate Cox regression analysis, hub genes co-expressed with differentially expressed BMPs/BMPRs were filtered out to improve the risk model and explore potential mechanisms. The improved risk model was re-established via LASSO combining hub genes with differentially expressed BMPs/BMPRs as the core. In the testing cohort including 93 lung adenocarcinoma patients, immunohistochemistry (IHC) was performed to verify BMP5 protein expression and its association with prognosis.

Results: BMP2, BMP5, BMP6, GDF10, and ACVRL1 were verified as downregulated in lung adenocarcinoma. Survival analysis identified BMP5 as an independent protective prognostic factor. We also found that BMP5 was significantly correlated with EGFR expression and mutations, suggesting that BMP5 may play a role in targeted therapy. The initial risk model containing only BMP5 showed a significant correlation (HR: 1.71, 95% CI: 1.28-2.28, p: 3e-04) but low prognostic accuracy (AUC of 1-year survival: 0.6, 3-year survival: 0.6, 5-year survival: 0.63). Seventy-nine hub genes co-expressed with BMP5 were identified, and their functions were enriched in cell migration and tumor metastasis. The re-established risk model showed greater prognostic correlation (HR: 2.58, 95% CI: 1.92-3.46, p: 0) and value (AUC of 1-year survival: 0.72, 3-year survival: 0.69, and 5-year survival: 0.68). IHC results revealed that BMP5 protein was also downregulated in lung adenocarcinoma and higher expression was markedly associated with better prognosis (HR: 0.44, 95% CI: 0.23-0.85, p: 0.0145).

Conclusion: BMP5 is a potential crucial target for lung adenocarcinoma treatment based on significant differential expression and superior prognostic value.

Keywords: bone morphogenetic protein receptors; bone morphogenetic proteins; lung adenocarcinoma; prognosis; risk model.