**1. Introduction**

Lung cancer is one of the most common causes of cancer-related deaths in the world. Despite recent advances in the early detection and treatment of lung cancer, the prognosis is very poor, partly because of a high rate of recurrence even after curative resection. Approximately half of the patients diagnosed with non-small cell lung cancer (NSCLC) develop recurrence and die of the disease even after curative resection. Adjuvant chemotherapy plays an important role in preventing recurrence following curative resection of lung cancer. A survival benefit of platinum-based adjuvant chemotherapy in NSCLC was confirmed by phase III trials and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis [1,2]. However, some NSCLC patients receiving such adjuvant chemotherapy show no progress in survival. Accordingly, it is critically important to identify biomarkers that can select patients who will not respond well to adjuvant therapy so that an appropriate treatment plan can be provided to patients. Given that occult micro-metastatic cancer cells might be present systemically at the time of surgery, altered expression of metastasis-related genes might be useful as molecular biomarkers to distinguish patients at high risk of recurrence after surgery.

Non-metastatic cells 1 (NME1), also known as NM23-H1, was the first metastasis suppressor discovered by its reduced mRNA transcript levels in a murine melanoma cell line exhibiting high metastatic activity [3]. In addition to its known function as a nucleotide-diphosphate kinase that converts nucleoside diphosphates to nucleoside triphosphates at the expense of adenosine triphosphate (ATP), NME1 is involved in several pathological processes such as motility and metastasis of tumor cells [4]. An inverse relationship between metastatic potential and NME1 expression has been reported in several types of cancers, including non-small cell lung cancer [5,6], melanoma [7], breast cancer [8], hepatocellular carcinoma [9], gastric cancer [10], and colorectal cancer [11]. Transfection of the *NME1* gene into different types of cancer cells has resulted in the inhibition of metastatic properties, including migration, invasion, and colonization [12–16]. *NME1* silencing is known to upregulate β-catenin-dependent TCF/LEF-1 (T-cell factor/lymphoid enhancer-binding factor) transactivation through glycogen synthase kinase (GSK)-3β-independent mechanisms by promoting nuclear translocation of β-catenin [17].

Activation of the canonical Wnt signaling pathway inhibits axin-mediated β-catenin phosphorylation and degradation and allows β-catenin to accumulate in the cytoplasm and then translocate into the nucleus. Nuclear β-catenin forms a stable complex with members of the TCF/LEF transcription factor family and induces the expression of target genes such as *c-MYC* and *CCND1*, and influences the metastatic cascade by regulating the expression of genes such as *AXIN2*, *SNAIL*, *ZEB1*, *COX2*, and *S100A4* [18]. It has been reported that the Wnt/β-catenin signaling pathway is involved in the invasion and metastasis of tumor cells in patients with NSCLC [19–22]. In addition to the nuclear translocation of β-catenin by *NME1* silencing, Wnt/β-catenin-mediated resistance to cisplatin has been demonstrated in human cancers [23,24]. Based on these reports, we hypothesized that NME1 and the Wnt signal may cooperatively affect patient prognosis and cisplatin treatment.

In this study, we analyzed whether the effect of NME1 on recurrence-free survival (RFS) can be modified by cisplatin-based adjuvant chemotherapy and β-catenin overexpression in early stage NSCLC.
