PPIB/Cyclophilin B expression associates with tumor progression and unfavorable survival in patients with pulmonary adenocarcinoma

Ilseon Hwang; Joon Seon Song; Eunho Cho; Kwon-Ho Song; Sang Hyun Ra; Chang-Min Choi; Tae Woo Kim; Sung-Han Kim; Jeong Won Kim; Joon-Yong Chung

doi:10.62347/TYNU2341

PPIB/Cyclophilin B expression associates with tumor progression and unfavorable survival in patients with pulmonary adenocarcinoma

Am J Cancer Res. 2024 Feb 25;14(2):917-930. doi: 10.62347/TYNU2341. eCollection 2024.

Authors

Ilseon Hwang¹, Joon Seon Song², Eunho Cho^{3

4

5}, Kwon-Ho Song⁶, Sang Hyun Ra⁷, Chang-Min Choi⁸, Tae Woo Kim^{3

4

5}, Sung-Han Kim⁷, Jeong Won Kim⁹, Joon-Yong Chung¹⁰

Affiliations

¹ Department of Pathology, Keimyung University School of Medicine, Dongsan Medical Center Daegu 42601, Republic of Korea.
² Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
³ Department of Biochemistry and Molecular Biology, Korea University College of Medicine Seoul 02841, Republic of Korea.
⁴ Department of Biomedical Science, Korea University College of Medicine Seoul 02841, Republic of Korea.
⁵ BK21 Graduate Program, Department of Biomedical Science, Korea University College of Medicine Seoul 02841, Republic of Korea.
⁶ Department of Cell Biology, Daegu Catholic University School of Medicine Daegu 42472, Republic of Korea.
⁷ Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
⁸ Department of Pulmonary and Critical Care Medicine and Oncology, Asan Medical Center, University of Ulsan College of Medicine Seoul 05505, Republic of Korea.
⁹ Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine Seoul 07441, Republic of Korea.
¹⁰ Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20852, USA.

Abstract

Cyclophilin B (CypB), encoded by peptidylprolyl isomerase B (PPIB), is involved in cellular transcriptional regulation, immune responses, chemotaxis, and proliferation. Recent studies have shown that PPIB/CypB is associated with tumor progression and chemoresistance in various cancers. However, the clinicopathologic significance and mechanism of action of PPIB/CypB in non-small cell lung cancer (NSCLC) remain unclear. In this study, we used RNA in situ hybridization to examine PPIB expression in 431 NSCLC tissue microarrays consisting of 295 adenocarcinomas (ADCs) and 136 squamous cell carcinomas (SCCs). Additionally, Ki-67 expression was evaluated using immunohistochemistry. The role of PPIB/CypB was assessed in five human NSCLC cell lines. There was a significant correlation between PPIB/CypB expression and Ki-67 expression in ADC (Spearman correlation r=0.374, P<0.001) and a weak correlation in SCC (r=0.229, P=0.007). In ADCs, high PPIB expression (PPIB^high) was associated with lymph node metastasis (P=0.023), advanced disease stage (P=0.014), disease recurrence (P=0.013), and patient mortality (P=0.015). Meanwhile, high Ki-67 expression (Ki-67^high) was correlated with male sex, smoking history, high pT stage, lymph node metastasis, advanced stage, disease recurrence, and patient mortality in ADC (all P<0.001). However, there was no association between either marker or clinicopathological factors, except for old age and PPIB^high (P=0.038) in SCC. Survival analyses revealed that the combined expression of PPIB^high/Ki-67^high was an independent prognosis factor for poor disease-free survival (HR 1.424, 95% CI 1.177-1.723, P<0.001) and overall survival (HR 1.266, 95% CI 1.036-1.548, P=0.021) in ADC, but not in SCC. Furthermore, PPIB/CypB promoted the proliferation, colony formation, and migration of NSCLC cells. We also observed the oncogenic properties of PPIB/CypB expression in human bronchial epithelial cells. In conclusion, PPIB/CypB contributes to tumor growth in NSCLC, and elevated PPIB/Ki-67 levels are linked to unfavorable survival, especially in ADC.

Keywords: Ki-67; Peptidylprolyl isomerase B; adenocarcinoma; non-small cell lung cancer; prognosis.