Apart from promoter methylation of WNT pathway inhibitors, methylation of the beta-catenin promoter has also been described that leads to loss of beta-catenin protein expression and a poor prognosis in NSCLC patients . Epigenetic modulation of the anti-aging Klotho  is also significant in carcinogenesis [100C102]. lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC represents 15C20% of all LC cases and is the more aggressive form; it metastasizes early and therefore surgical intervention is usually rarely a therapeutic option . On the other hand, NSCLC denotes 80C85% and can be further classified into adeno (AC)-, squamous cell (SCC) -, large cell (LCC) and various mixed type carcinomas . Unfortunately, the majority of NSCLC patients are diagnosed at an advanced stage of the AM 580 disease narrowing down therapeutic options and leading to a limited median survival of about 18?months . Recent studies have confirmed that therapy-surviving cancer stem cells (CSC) play a cardinal role in drug resistance and therefore, rapid progression of the disease . While the carcinogenic process in the lung can be traced back to genetic mutations, malfunctioning signaling pathways are also highly important modulators of tumor formation and individual features of the disease. An increasing amount of evidence has shown that this WNT pathway is one of the main signaling pathways involved in maintaining lung homeostasis and that aberrant activation of this pathway may underlie several debilitating lung diseases. Similarly, to other human cancers, WNT signaling plays an important part in lung carcinogenesis. Interestingly, however, while some epigenetic changes that affect WNT pathway inhibitors are similar to those seen in other malignancies, genetic mutations of the WNT pathway are uncommon in NSCLCs . This review will summarize some novel aspects of WNT signaling, what is currently known about WNT associated LC pathogenesis as well as some important features of WNT mediated events in LC therapies. The complexity of WNT signaling C Canonical and non-canonical WNT signaling pathways WNT CAPN1 proteins are secreted glyco-lipoprotein morphogens that are required during lung development for cell-fate specification, cell proliferation and the control of asymmetric cell division. In adults, WNT signaling is essential for stem cell maintenance for regulation of tissue homeostasis . Most of the 19 WNT ligands and the 10 main receptors, Frizzleds (FZD) that have been identified in mammalian cells can be identified in the human lung AM 580 [9, 11]. The two main different WNT pathways include i) the beta-catenin-dependent or canonical pathway, and ii) the beta-catenin-independent or non-canonical pathways including the planar cell polarity (PCP) and the WNT/Ca2+ pathways (Fig.?1). Open in a separate windows Fig. 1 Multiplicity of canonical (a) and non-canonical (b) WNT pathways. Binding of WNT ligands to individual or different combination of their receptors including FZD and LRP5/6, or FZD in combination with ROR1, ROR2 or RYK activate multiple beta-catenin dependent (a) and beta-catenin-independent pathways (b) Canonical or beta-catenin dependent WNT signaling. In the lung, the role of WNT signaling has been examined in detail by multiple studies which mostly focus on beta-catenin-dependent signaling. In the canonical pathway during the absence of WNT, a beta-catenin destruction complex is assembled, consisting of: Axis inhibition protein (AXIN), adenomatous polyposis coli (APC), and glycogen synthase kinase 3-beta (GSK-3-beta) whereby beta-catenin is usually phosphorylated at serine and threonine sites and then proteolytically degraded [9, 12]. If WNT is usually available to bind to one of the ten FZD receptors then a receptor complex between WNT, FZD, lipoprotein receptorCrelated protein (LRP), Disheveled (DVL), and AXIN is usually formed . Within this active complex, DVL becomes phosphorylated and eventually inhibits GSK-3-beta resulting in reduced phosphorylation and consequently stops the proteolytic destruction of AM 580 beta-catenin. Beta-catenin subsequently accumulates in the cytoplasm. The cytoplasmic beta-catenin can then migrate to the nucleus and forms a complex with members of the T-cell AM 580 factor (TCF)/Lymphoid enhancer-binding factor (LEF) family of transcription factors and transcriptional coactivators including cAMP response element-binding protein (CREB)Cbinding protein (CBP) and p300. The many target genes include c-myc and cyclin D1 . The transmembrane receptor tyrosine kinase orphan receptor ROR2 (which is usually important in non-canonical WNT signaling) may also be involved in canonical signaling via interactions with FZD2 . ROR2 , as well as the other WNT-binding receptors such as receptor-like tyrosine kinase RYK , can therefore act as regulatory receptors for the beta-catenin dependent WNT signaling. Non-canonical WNT signalingThe two non-canonical WNT pathways are activated by several WNT ligands including WNT4, WNT5a, WNT7a, WNT11 and WNT16 [16C18]. Activation of the PCP signaling pathway, for example by WNT11, leads to the activation of the small GTPases RhoA (RAS homologue gene-family member A) and RAC1 (Ras-related.