Thyroid hormone receptor interactor 13 (TRIP13) overexpression associated with tumor progression and poor prognosis in lung adenocarcinoma

Highlights

• TRIP13 is highly overexpressed in lung adenocarcinoma cells.

• TRIP13 expression is positively associated with tumor size, T-stage, and N-stage.

• Heightened TRIP13 expression is associated with lower overall survival.

• TRIP13 promotes proliferation and inhibits apoptosis and G2/M phase shift.

• TRIP13 is involved in regulating dsDNA break repair and PI3K/Akt signaling.

Abstract

Thyroid hormone receptor interactor 13 (TRIP13) is an AAA⁺-ATPase that plays a key role in mitotic checkpoint complex inactivation and is associated with the progression of several cancers. However, its role in lung adenocarcinogenesis remains unknown. Here, we report that TRIP13 is highly overexpressed in multiple lung adenocarcinoma cell lines and tumor tissues. Clinically, TRIP13 expression is positively associated with tumor size, T-stage, and N-stage, and Kaplan-Meier analysis revealed that heightened TRIP13 expression is associated with lower overall survival. TRIP13 promotes lung adenocarcinoma cell proliferation, clonogenicity, and migration while inhibiting apoptosis and G2/M phase shift in vitro. Accordingly, TRIP13-silenced xenograft tumors displayed significant growth inhibition in vivo. Bioinformatics analysis demonstrated that TRIP13 interacts with a protein network associated with dsDNA break repair and PI3K/Akt signaling. TRIP13 upregulatesAkt^Ser473 and downregulatesAkt^Thr308/mTOR^Ser2448activity, which suppresses accurate dsDNA break repair. TRIP13 also downregulates pro-apoptotic Bad^Ser136 and cleaved caspase-3 while upregulating survivin. In conclusion, heightened TRIP13 expression appears to promote lung adenocarcinoma tumor progression and displays potential as a therapeutic target or biomarker for lung adenocarcinoma.

Introduction

Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, accounts for 80–85% of all lung cancer cases [1,2]. NSCLC includes lung adenocarcinomas, large cell carcinomas, and squamous cell carcinomas (SCCs), with lung adenocarcinoma being the most common NSCLC type [3,4]. Although SCC and SCLC rates are declining, lung adenocarcinoma incidence continues to rise globally, particularly among females [4]. Unfortunately, the overall prognosis of lung adenocarcinoma patients remains poor, with an overall five-year survival rate of only 15% [5]. Studies have shown that oncogene activation, mutations in tumor suppressor genes, somatic mutations, and/or genomic rearrangements underlie lung adenocarcinogenesis [6]. Therefore, elucidating the functions of abnormally-expressed genes specific to lung adenocarcinoma is of great importance to revealing the disease's pathogenesis and developing more efficacious treatments.

The thyroid hormone receptor interacting protein 13 (TRIP13) is expressed in a variety of adult tissues, most notably in the meiotically-active testis and oocytes [7]. TRIP13 encodes a 432-residue AAA⁺-ATPase that plays a key role in mitotic checkpoint complex (MCC) inactivation [8]. TRIP13 gain-of-function causes premature MCC inactivation, while TRIP13 loss-of-function delays the metaphase-to-anaphase cell cycle transition [8]. In recent years, TRIP13 has become associated with the occurrence and development of malignant tumors. TRIP13 overexpression produces malignant transformation in non-malignant SCC cells in vitro [9]. Clinically, TRIP13 expression is significantly upregulated in 12 cancer types, and heightened TRIP13 expression signals inferior prognosis in breast, liver, gastric, and NSCLC patients [10].

That being said, TRIP13's role in the development of NSCLC is still poorly understood. A comparative genomic hybridization analysis of NSCLC tumors revealed that the gain of chromosomal region 5p15.33 (which contains the TRIP13 gene) was the most common early molecular event in NSCLC [11]. The foregoing evidence suggests that TRIP13 may be potent oncogene underlying the development of lung adenocarcinoma. Therefore, the aim of this study was to elucidate the role of TRIP13 in lung adenocarcinoma cells and elucidate the mechanism(s) by which TRIP13 affects lung adenocarcinoma cells.