Since lung cancer has no symptoms in the early stage, majority of patients are already in the advanced stage when they are discovered. Although traditional treatments are constantly improving, the five-year survival rate of lung cancer is only 19% (Siegel et al. 2019). GI has been reported in various malignant cancers, including lung cancers (Bartkova et al. 2005, de Bruin, McGranahan, Mitter, Salm, Wedge, Yates, Jamal-Hanjani, Shafi, Murugaesu, Rowan, Grönroos, Muhammad, Horswell, Gerlinger, Varela, Jones, Marshall, Voet, Van Loo, Rassl, Rintoul, Janes, Lee, Forster, Ahmad, Lawrence, Falzon, Capitanio, Harkins, Lee, Tom, Teefe, Chen, Begum, Rabinowitz, Phillimore, Spencer-Dene, Stamp, Szallasi, Matthews, Stewart, Campbell and Swanton 2014, Ding et al. 2008, Gorgoulis et al. 2005, How, Bruce, So, Pintilie, Haibe-Kains, Hui, Clarke, Hedley, Hill, Milosevic, Fyles and Liu 2015, Jamal-Hanjani et al. 2017, Nagahashi et al. 2016, Negrini, Gorgoulis and Halazonetis 2010, Varella-Garcia 2010). CIN is the major type of GI in lung cancer, which leads to the high gene mutation burden by chromosome structure and number alterations in cancer cells (Negrini, Gorgoulis and Halazonetis 2010). In this study, we found that a total of 185 GI-associated lncRNAs were significantly differentially expressed. Functional analysis revealed that GI-associated pathways were significantly enriched, which indicates that GI-associated lncRNAs may be associated with tumorigenesis. 5 GI-associated lncRNAs significantly associated with OS. A novel prognostic model integrating 5 GI-associated lncRNAs was firstly constructed and differentiate different risk group.
Among the 5 GI-associated lncRNAs, 4 of them, including AC012085.2, FAM83A-AS1, MIR193BHG, LINC01116, acted as risk factors for LUAD, and MIR223HG was a protective factor. FAM83A-AS1 was up-regulated in lung cancer tissues and enhances the proliferation, migration, invasion, and epithelial-mesenchymal transition of LUAD (Braicu et al. 2019, Shi et al. 2019, Xiao et al. 2019). IR193BHG was elevated and showed good clinical values for diagnosing early-onset preeclampsia (Zhang et al. 2020). LINC01116 mediated gefitinib resistance of NSCLC cells by affecting IFI44 expression (Wang et al. 2020). LINC01116 overexpressed in lung cancer tissues and cell lines and was significantly associated with proliferation and metastasis (Fan et al. 2020, Wang, Lu, Ren, Wu, Wang, Yan and Wang 2020, Zeng et al. 2020). MIR223HG, acting as a competing endogenous RNA, inhibited acute myeloid leukemia progression by inducing IRF4 expression (Mangiavacchi et al. 2016). These studies were consistent with our results. However, the role of AC012085.2 was unclear and need be further explored.
KEGG and GO enrichment analysis indicated that genes co-expressed with the 185 GI-related lncRNAs in the high-risk and low-risk LUAD patients identified in this study were not only enriched in many biological processes, such as metabolic process and oxidoreductase activity, they were also enriched in critical GI-related pathways, including cilium movement pathway, microtubule motor activity pathway, chromosomal region pathway, and cell cycle pathway. Dyskinesia and structural abnormalities of cilia can cause GI and lead to the occurrence of cancer (Remo et al. 2020). Chromosome segregation requires stable microtubule attachment at kinetochores, when the dynamic of microtubules is insufficient and the orientation is deviated, it can lead to GI in human cells (Bakhoum, Genovese, et al. 2009, Bakhoum, Thompson, et al. 2009). The mechanisms of GI also include extra centrosomes (Ganem et al. 2009), mutations of mitotic checkpoint genes (Cahill et al. 1998), faulty cell-cycle regulation (Hernando et al. 2004, Rajagopalan et al. 2004, Sotillo et al. 2010), and chromatid cohesion (Barber et al. 2008). The mechanism of GI is very complicated and needs be further studied.
Meanwhile, there are several limitations to our study. (1) Due to the limited lncRNA chip of LUAD, we could only divide the TCGA data set into training set and validation set randomly and more independent data sets are needed to validate the GILncSig to ensure its robustness and reproducibility. (2) In vivo and in vitro experiments were not performed to verify the role of the GILncSig model, therefore, subsequent experiments are needed to validate the reliability of results. (3) As an observational study, confounding factors, such as pharmaceutical treatment, exposure to environmental tobacco smoking, residential radon, cooking oil fumes, PM2.5 and so on, may have an impact on our results.