We showed that LINC00240 was downregulated in a lung cancer cell line after miR-7-5p mimic transfection. Further investigations revealed that the knockdown of LINC00240 induced the overexpression of miR-7-5p. The qverexpression of miR-7-5p diminished cancer invasion and migration. The EGFR expression was down regulated after miR-7-5p treatment. Silencing LINC00240 suppressed the invasion and migration of the lung cancer cells, whereas LINC00240 overexpression exerted an opposite effect. Furthermore, the lower expression of LINC00240 in squamous lung cancer was analyzed using TCGA data.
Long noncoding RNAs (lncRNAs) are functionally defined as transcripts > 200 nt in length with no protein-coding potential, many of which are uniquely expressed in differentiated tissues or specific cancer types [21]. Long noncoding RNAs participate in the regulation of a variety of cell activities, such as cell differentiation, proliferation, invasion, apoptosis and autophagy, through interacting with RNAs, DNAs or proteins [22]. They play important roles in chromatin remodeling, transcriptional repression and post-transcriptional regulation [23]. It is now widely understood that lncRNAs serve as signals of specific cellular states or readouts of active cellular programs [24]. The molecular mechanisms of lncRNAs are traditionally classified into four archetypes: signals, decoys, guides and scaffolds. Several lncRNAs possess characteristics from multiple archetypes that, in combination, are critical to their eventual biological function. Recent studies revealed that some lncRNAs assumed the role of molecular sponges, a behavior akin to that of competitive endogenous RNAs (ceRNAs), through miRNAs binding sites, and subsequently repressed their inhibitory effect on their natural targets [25].
Moreover, lncRNAs have been observed to regulate complex cellular activities that are typically deregulated in cancer (e.g., cell growth, differential expression, and the maintenance of cell identity) [26]. The overexpression of the HOTAIR lncRNA in early-stage, surgically resected breast cancer was highly predictive of progression to metastatic disease and overall survival [27]. Subsequent studies showed that HOTAIR deregulation was associated with cancer progression in 26 human tumor types [28]. By overlapping the cancer susceptibility loci determined by genome-wide association studies (GWAS), the presence of lncRNAs in specific tumors can also be examined. For instance, association analysis of the known risk loci certified through the genotyping of cancer patients elucidated the existence of a certain relationship between ANRIL, glioma, and basal cell carcinoma as well as an association of PTCSC3 with thyroid cancer [29, 30].
As small noncoding RNAs, microRNAs or miRNAs post-transcriptionally suppress cancer-related genes through attachment to the 3’-UTR of target mRNAs and thus act as oncogenes or tumor suppressor genes themselves[31]. MicroRNAs are involved in a range of processes that includes development, differentiation, proliferation, and apoptosis [32–34]. Multiple studies have shown that miRNAs play key roles in the metastasis of certain cancers, including gastric cancer, breast cancer, hepatocellular carcinoma, bladder cancer and lung cancer. Accumulating evidences has confirmed the indispensable role played by lncRNA sponges in cancer progression. Regarding lung cancer, the up regulation of a potent oncogene, ERBB4, generated by UCA1 was achieved by binding miR-193-3p [35]. In contrast, the sequestration of miR-181-a enabled MEG3 to up-regulate Bcl-2 in the case of gastric cancer [36]. In endometrial cancer stem cells, linc-RoR bound miR-145 in a similar manner, and ZFAS1 bound miR-150 in hepatocellular carcinoma. Likewise, CASC2 controlled the degree of miR-21 concentration [37]. Linc-RNA-RoR’s sponge-like behavior was determined to inhibit the miRNA-145 mediated differentiation of endometrial cancer stem cells[38]. Long non-coding RNA CASC2 suppressed malignancy in human gliomas by miR-21 [39]. The development of RNA-targeting therapeutics provides tremendous opportunities to modulate lncRNAs for anti-cancer purposes. While several strategies have been successfully employed to deplete lncRNAs, prior knowledge of lncRNA cellular localization is critical for selecting the appropriate strategy to achieve robust lncRNA modulation [40].
The role of LINC00240 has been reported in esophageal squamous cell carcinoma (ESCC). The “loss” of miR-26b-5p-mediated LINC00240-KLF3 crosstalk was probably implicated in the tumorigenesis of ESCC [41]. LINC00240 acts as an oncogene in cervical cancer progression by modulating the miR-124-3p/STAT3/MICA axis. The loss of LINC00240 suppressed cervical cancer development through the sponging of miR-124-3p and the overexpression of LINC00240 induced cervical cancer development. LINC00240 expression promoted cervical cancer progression via the induction of miR-124-3p/STAT3/MICA-mediated NKT cell tolerance [42]. This study showed that the lncRNA of LINC00240 sponged miR-7-5p, which is implicated in EGFR down-regulation.
Epidermal growth factor receptor (EGFR), a member of the Erb B receptor family, is widely expressed in human tissues and regulates important cellular processes, including proliferation, differentiation, and development. The establishment, growth and upkeep of epithelial tissues are primarily attributed to the EGFR signaling network, alterations in which may trigger malignant transformation [43]. One of the dysregulated miRNAs, miRNA-7-5, has displayed its potential utility as a tumor suppressor in gastric cancers, breast cancers, and colorectal cancers [44–46]. miR-7-5p coordinately regulates EGFR signaling at multiple levels, suggesting that miR-7-5p additionally regulates a number of other cellular pathways relevant to normal and tumor cells and its ability to regulate oncogenic EGFR signaling in multiple cancer cell line models suggests that the therapeutic up-regulation of miR-7-5p expression in these tumors may inhibit growth and metastasis [12]. miR-7-5p suppresses the growth of lung cancer cells through others EGFR pathway. miR-7 targets RAF1, IRS-2, BCL-2, and PA28γ in lung cancer cells. In addition, miR-7 can increase the sensitivity of treatment resistant cancer cells to therapeutics and inhibit metastasis. These data suggest that replacement of miR-7-5p in specific human cancers could represent a new treatment approach [11].
While adenocarcinoma and squamous cell cancer are classified as NSCLC, these two carcinomas are distinguished from each other in terms of their respective occurrence at different anatomical sites as well as their molecular biologic background related to genetics and epigenetics. In the case of adenocarcinoma, in particular, driver mutations and the corresponding drugs already exists and thus, it reacts well to targeted therapy, which includes, but is not limited to EGFR, ALK, and ROS1, resulting in good outcomes. In contrast, appropriately targeted therapy drugs are yet to be identified for squanmous cell cancer. EGFR overexpression or amplification occurs more frequently in squamous cell carcinoma than in adenocarcinoma, but EGFR mutations occurs mostly in adenocarcinoma. The significantly different expression of LINC00240 only in squamous cell cancer provides clues to explaining the augmented EGFR expression, drawing on the findings of high expression of EGFR and marginal EGFR mutations in squamous cell cancer. In addition, the discovery of EGFR signaling pathway inhibition through lncRNA can shed light on the mechanism as a new potential target for lung cancer treatment.