Overexpression of T‐LAK cell‐originated protein kinase predicts poor prognosis in patients with stage I lung adenocarcinoma

Abstract

Tumor recurrence is the most common cause of disease failure after surgical resection in early-stage lung adenocarcinoma. Identification of clinically relevant prognostic markers could help to predict patients with high risk of disease recurrence. A meta-analysis of available lung adenocarcinoma microarray datasets revealed that T-LAK cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is overexpressed in lung cancer. Using stable cell lines with overexpression or knockdown of TOPK, we have shown that TOPK can promote cell migration, invasion, and clonogenic activity in lung cancer cells, suggesting its crucial role in lung tumorigenesis. To evaluate the prognostic value of TOPK expression in resected stage I lung adenocarcinoma, a retrospective analysis of 203 patients diagnosed with pathological stage I lung adenocarcinoma was carried out to examine the expression of TOPK by immunohistochemistry (IHC). The prognostic significance of TOPK overexpression was examined. Overexpression of TOPK (IHC score >3) was detected in 67.0% of patients, and these patients were more frequently characterized with disease recurrence and angiolymphatic invasion. Using multivariate analysis, patient age (>65 years old; P = 0.002) and TOPK overexpression (IHC score >3; P < 0.001) significantly predicted a shortened overall survival. Moreover, TOPK overexpression (IHC score >3; P = 0.005) also significantly predicted a reduced time to recurrence in the patients. Our results indicate that overexpression of TOPK could predetermine the metastatic capability of tumors and could serve as a significant prognostic predictor of shortened overall survival and time to recurrence. (Cancer Sci 2012; 103: 731-738) L ung cancer is the leading cause of cancer-related death worldwide. The incidence of adenocarcinoma, the most common histological subtype of non-small-cell lung carcinoma (NSCLC) in most countries, has increased in both sexes during the past several decades, whereas squamous cell carcinoma has decreased.(1,2) Surgical resection is the main treatment of choice for early-stage NSCLC.(3) Although patient survival after stage I NSCLC resection is good, postoperative recurrence has been reported to occur in 22-38% of patients. The survival rate is poor in patients with recurrence following resection of stage I NSCLC. (6,8) Many randomized clinical trials have evaluated the role of adjuvant chemotherapy in patients with resected stage I NSCLC and have tried to identify patients with a higher risk of recurrence or poor prognosis after surgical resection.(9-11) Investigation of biomarkers of early-stage NSCLC may be helpful in designing clinical trials for adjuvant chemotherapy in the future. T-LAK cell-originated protein kinase (TOPK), also known as PDZ-binding kinase (PBK), is a MAPKK-like serine/threonine protein kinase that was identified as an interleukin-2-induced gene in T-LAK cells and as an interaction partner with the human tumor suppressor hDlg, identified by yeast two-hybrid screening. (12,13) TOPK is bar...

PBK/TOPK expression in non‐small‐cell lung cancer: its correlation and prognostic significance with Ki67 and p53 expression

“…These results are similar to those reported by Shih et al . Wei et al . found that overexpression of PBK/TOPK predicted the metastatic capability of tumours, and could serve as a significant prognostic predictor in lung adenocarcinoma.…”

PBK/TOPK expression correlates with mutant p53 and affects patients' prognosis and cell proliferation and viability in lung adenocarcinoma

“…Furthermore, TOPK and mutant p53 were demonstrated to be independent prognostic factors in lung adenocarcinoma. These observations are partly consistent with the primary findings that patients with TOPK overexpression had a significantly poorer prognosis in stage I lung adenocarcinoma [16]. Zlobec and colleagues [18] also found that TOPK was a valuable prognostic factor in colorectal cancer.…”

“…For example, TOPK is involved with highly proliferative cells and tissues and is highly expressed in many types of tumors such as lymphoma, leukemia, breast cancer, Ewing sarcoma, and colorectal cancer [6][7][8][9][10]. High TOPK expression can promote cell proliferation [11][12][13] and prevent apoptosis [14,15] and is associated with a poor prognosis [16][17][18][19]. Moreover, TOPK expression may play an important role in the progress of cytokinesis and inflammation [20][21][22].…”

CDK1-mediated mitotic phosphorylation of PBK is involved in cytokinesis and inhibits its oncogenic activity

“…Overexpression of PBK has been associated with increased tumorigenicity and clinical lethality of various cancers [3,9,10,12,37]. Future experiments are also needed to further investigate the relationship between the levels of PBK protein and PBK mitotic phosphorylation in cancer patient samples.…”

“…In addition, PBK overexpression is sufficient to transform mouse epidermal cells [11] and is strongly associated with patient survival and tumor grade [3,9,12]. Several studies have shown that PBK knockdown decreases cell viability and proliferation [7,11,13–16] as well as suppressing the cologenic potential of cancer cells [7,10,11,15]. …”