Here we focus on finding BMI-associated lncRNAs in tumor-adjacent tissues of lung cancer, therefore, identifying the lncRNAs linking both obesity and lung cancer. Most lncRNA is expressed in a cell-, tissue- and situation-specific manner. For instance, different lncRNAs were identified in association with chemosensitivity, radiosensitivity, and EGFR-targeted therapy sensitivity (21). As far as is known, this is the first study to emphasize lncRNAs in tumor-adjacent tissues. It has been reported that signals detected from tumor-adjacent tissues could build a superior prognosis model and better predict cancer recurrence (22, 23) because 40% of these tissues already exhibited aberrant genomic features (24). We hope that analyzing lncRNAs from these tissues can 1) explore the tumor microenvironment where signals from the tumor and surrounding adipose can be better captured; 2) identify the secretions present in tumor-adjacent cells that could be detected in peripheral blood.
Numerous studies have been published to support the relationship between TM4SF19-AS1 and tumors, indicating its biomarker potential. Several studies have concluded that TM4SF19-AS1 was a top upregulated lncRNA in head and neck squamous cell carcinoma, especially in laryngeal squamous cell carcinoma (LSCC), with data collected in TCGA (25, 26). A further study found that in LSCC, TM4SF19-AS1 was positively correlated with tumor-node-metastasis stage and lymph node metastasis. This study also suggested that the knockdown of TM4SF19-AS1 suppressed the proliferation, migration, and invasion of LSCC cells (27). Moreover, together with other lncRNAs, TM4SF19-AS1 was used to construct prognosis models with good discriminative ability in esophageal, bladder and gastric cancer (28–30).
As described previously, TM4SF19-AS1 was estimated to involve in metabolic, immune response, and cancer-related pathways such as MTOR1 and MYC. A single-cell study examining T cells in cancer immunity recently annotate TM4SF19-AS1 as a signature lncRNA for both CD8 effector and CD4 effector T cells (31). The author noted that effector signature lncRNAs were often associated with T cell proliferation involved in immune response, positive regulation of cytokine secretion, and positive regulation of cytolysis. According to the enrichment analysis performed in this manuscript, TM4SF19-AS1 was significantly enriched in chemotaxis (p = 4.64E-48), smoothened signaling pathway (3.62E-33), G-protein coupled receptor signaling pathway (p = 4.5E-31), cellular response to cholesterol (p = 1.09E-30), cell adhesion (p = 5.25E-27), positive regulation of macrophage chemotaxis (p = 1.84E-12) and regulation of tumor necrosis factor biosynthetic process (3.75E-11). With the growing number of single-cell immune-related data available, the function of TM4SF19-AS1 in cancer immunity, and its potential impact on both obesity and lung cancer, would come to clear soon.
There are several limitations in the present study. First, the sample size of the validation study is small. As a matter of fact, it is difficult to identify lung cancer patients with obesity in Asia. Secondly, we used BMI to define obesity, which is not capable to measure muscle-adiposity ratio or body fat distribution. And lastly, we used RNA bulks data to detect lncRNA signals which may limit the discovery of cell type-specific lncRNAs.