High KIF2A expression promotes proliferation, migration and predicts poor prognosis in lung adenocarcinoma

Highlights

• KIF2A expression is significantly up regulated in LUAD tissues and associated with TNM stage.

• Knockdown KIF2A inhibits cell migration and is associated with EMT.

• Silencing KIF2A decreases cell proliferation by preventing cell cycle progression.

• Knockdown KIF2A inhibits cell proliferation and induces apoptosis through the PI3K/AKT, MAPK/ERK signaling pathway.

Abstract

The Kinesin family member 2a (KIF2A), that belongs to the Kinesin-13 microtubule depolymerases, plays an important role in cancer cell proliferation, migration and apoptosis in various types of cancer such as gastric cancer, breast cancer, and squamous cell carcinoma of the oral tongue, but, its role and mechanism in lung adenocarcinoma (LUAD) is largely unknown. The present study reported that KIF2A was overexpressed in LUAD tissues as compared with adjacent normal tissues. KIF2A was closely correlated with TNM stage and lymph node metastasis (P < 0.01), whereas, no similar relationships between KIF2A and age, gender, smoking and differentiation. Multivariate analysis indicated that hyperexpression of KIF2A in LUAD was an independent risk factor for worse overall survival in LUAD patients (HR: 3.135, 95%CI: 1.331–7.112, p < 0.05). In vitro, KIF2A knockdown markedly reduced LUAD cell A549 migration and could regulate epithelial-mesenchymal transition. Furthermore, silencing KIF2A inhibited cell proliferation and induced apoptosis in lung adenocarcinoma(LUAD) cells. In conclusion, KIF2A may serve as a valuable prognostic indicator and promising therapeutic target of LUAD.

Introduction

Lung cancer has become the first cause of cancer-related deaths globally [1]. It accounts for 26% of all cancer deaths in the United States. In contrast to the steady rise up in survival for most cancers, the survival rate of increase has been slow in lung cancer, for which the 5-year relative survival is currently 18% [2]. In recent year, lung adenocarcinomas (LUAD) has become the most common lung subtype (43% in men and 52% in women) [3]. Although using CT to detect lung cancer among former or current heavy smokers has been shown to reduce lung cancer mortality by 20% in USA [4]; but, due to the infrastructure, technical expertise, and cost involved, it is impossible that this method will benefit those in lower-resource countries in the near future [1].Additionally, the malignant progression of lung cancer is associated with the interactions of frequently altered genes with signaling and transcriptional programs [5]. Hence, it is extremely necessary to look for sensitive molecules as predictive biomarkers and therapeutic targets for LUAD.

Kinesin superfamily proteins (KIFs)was firstly discovered in 1985 [6]. In mammals such as human and mouse, the total number of KIF genes is 45, including three M-KIFs (KIF2A, KIF2B, and KIF2C) and three C-KIFs (KIFC1, KIFC2,and KIFC3) [7]. Microtubules (MTs), as the vital components of the cytoskeleton, are essential not only for mitotic activity of malignant cells but also for invading neighboring tissues and causing distant metastasis [8]. The decrease and depolymerization of MTs are associated with the metastatic potential of the malignant tumors. The kinesin-13 family members, including kinesin superfamily protein 2A (KIF2A) and KIF2B, and the mitotic centromere-associated kinesin (MCAK), are M-type nonmotile microtubule depolymerases and play central role in regulating microtubule dynamics during mitotic progression [9,10]. Currently, mounting evidence suggests that KIF2A is abnormally expressed in many cancers, including Gastric Cancer, squamous cell carcinoma of the oral tongue (SCCOT), breast cancer, human glioma and hepatocellular carcinoma, and is involved in a number of cellular processes including proliferation, apoptosis, migration, and invasion [[11], [12], [13], [14], [15]]. However, the effect of KIF2A in lung adenocarcinoma carcinogenesis and its possible use as a tumor marker remain unclear.

In this research, our results demonstrate that KIF2A plays a crucial role in LUAD growth and progression and could serve as an important biomarker for predicting LUAD prognosis in the clinic. Our study also investigated the oncogenic mechanism of KIF2A.