Xiaoji Decoction XJD has been used

Xiaoji Decoction (XJD) has been used in the treatments of lung cancer for many years (Chai et al., 2014) and mechanistically has been shown to inhibit the growth of NSCLC Zinc protoporphyrin IX in vitro and in vivo (Chai et al., 2014). However, the mechanistic details of the potential therapeutic benefits of XJD for patients with lung cancer have not been well described. We previously observed that XJD inhibited proliferation of NSCLC cells via AMP-activated protein kinase alpha (AMPKα)-mediated inhibition of transcription factor SP1 protein levels followed by suppressing DNA methyltransferase 1 (DNMT1) expression both in vitro and in vivo (Zhao et al., 2016). However, multiple compounds and complicated metabolic processes of XJD may affect a variety of pathways and interactions of potential targets. Thus, the underlying molecular mechanisms associated with the therapeutic potential of XJD, including its action to sensitize the effect of gefitinib on cancer have not been fully elucidated. Long noncoding RNAs (lncRNAs) are transcripts >200 nucleotides with no protein-coding potential and play important roles in cancer biology. Of the characterized lncRNAs, the HOX transcript antisense intergenic RNA (HOTAIR), an approximately 2.2 kb long noncoding RNA transcribed from the HOXC locus, is regarded as an oncogene, and can reprogram chromatin organization and promote tumor progression (Botti et al., 2017). Overexpression of HOTAIR has been observed in several types of human cancers and is linked to tumor invasion, progression, metastasis, and poor prognosis through multiple signaling mechanisms. The important role of HOTAIR in cancer biology has stimulated interest in HOTAIR as a potential therapeutic target (Loewen et al., 2014; Lu et al., 2017; Malek et al., 2014; Wu et al., 2014). HOTAIR can mediate a physical interaction between Snail, a transcription factor and a master regulator of epithelial-to-mesenchymal transition (EMT), and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2. HOTAIR is a crucial player in Snail-mediated EMT in epithelial and hepatic morphogenesis (Battistelli et al., 2017). In addition, HOTAIR has been explored as a biomarker in lung cancer because its elevated expression is correlated with metastasis, drug resistance, and poor survival in patients with lung cancer (Loewen et al., 2014). Nevertheless, the potential impact of this lncRNA on the occurrence, growth, and progression of lung malignancy still remain to be determined. Prostaglandin E2 (PGE2) is involved in several biological processes such as renal function, inflammation, angiogenesis, and tumor growth. The various biological effects of PGE2 are mediated by the so-called E-type prostanoid receptors (EP1 to EP4). Among these, the EP4 receptor has been well studied in cancer. PGE2-mediated stimulation of EP4 triggered multiple signaling pathways and led to diverse patho-physiological responses (Tonisen et al., 2017). Activation and/or high expression of EP4 were observed in several malignancies including lung cancer, and associated with growth, progression, and overall survival (Bhooshan et al., 2016; Nandi et al., 2017; Parida et al., 2016; Tveteraas et al., 2012; Zhang et al., 2017). We previously observed that natural phytochemicals from traditional medicinal plants such as solamargine inhibited the growth of NSCLC cells through the inhibition of EP4 gene expression and its downstream targets (Chen et al., 2015; Huang et al., 2017). These results indicated an important role of EP4 in lung cancer growth and progression. However, the functional links between lncRNAs and EP4 have not been described and the detailed role of EP4 in lung cancer occurrence and progression still remains to be determined.