Lung cancer is one of the most common causes of cancer-related death worldwide [24]. Among them, LUAD is the major histological subtype of lung cancer, with incidence increasing year by year [25]. However, the outcome for LUAD patients is far from satisfaction due to the delay in early diagnosis [26]. Although radiotherapy, chemotherapy, surgery, and targeted therapy has significantly improved the survival rate of LUAD patients, it remains a serious global public health issue [27]. Therefore, it is urgent to find new diagnostic biomarkers and therapeutic targets for LUAD.
SNARE proteins are composed of 20–30 kDa proteins with a homologous domain of 60–70 amino acid residues [28]. SNARE proteins can be divided into Q-SNARE and R-SNARE based on difference in amino acid residues. In mammals, the SNARE family consists of more than 30 members with different subcellular localizations and forms specific SNARE complexes to regulate various cellular biological processes [29]. YKT6 belongs to R-SNARE protein family, highly conserved from yeast to humans[11]. YKT6 has been reported to be involved in vesicular transport, secretory, endocytosis, autophagy, and the formation and release of exocrine bodies [30]. Moreover, YKT6 is related to tumor progression; however, there are few research report on YKT6 in LUAD. In this study, bioinformatics analysis and cell function assays were used to explore the expression, prognosis, and possible biological roles of YKT6 in LUAD.
In the present study, YKT6 mRNA/protein was highly expressed in LUAD, correlated with clinical stage, lymph node metastasis, smoking history, and TP53 mutation in LUAD. YKT6 expression showed the highest in clinical stage III and lymph node metastasis stage IV, suggesting an important role in middle and late stages of LUAD. Thus, YKT6 may be used as a potential indicator of LUAD stages. Besides, compared to the expression in TP53-non-mutated LUAD samples, YKT6 showed elevated level in TP53-mutated tissues. Therefore, YKT6 might play an important role in the progression of LUAD through the TP53 pathway. In addition, YKT6 was significantly correlated with OS, DSS and PFI, suggesting a potential prognostic biomarker of LUAD.
Among the top ten hub genes (CDC20, PLK1, CDCA8, TPX2, KIF2C, KIF23, KIF4A, FOXM1, MCM7 and CDCA5) selected of YKT6 co-related genes, cell division cycle 20 (CDC20) promotes the resistance of glioblastoma (GBM) cells to chemotherapy and radiotherapy, while knockout of CDC20 can enhance the sensitivity of GBM cells to radiotherapy and chemotherapy by regulating the pro-apoptotic protein Bim [31].The polo-like kinase 1 (PLK1) is a serine/threonine protein kinase with a key role in eukaryotic cell division, DNA replication, and TP53 regulation [32]. PLK1 can promote the progress of Kras/TP53-mutated LUAD by regulating the transcriptional activation receptor RET [33]. In addition, PLK1 is overexpressed in hepatocellular carcinoma (HCC), related to tumor invasiveness and poor prognosis [34]. Cell division cycle-related genes 8 (CDCA8) and CDCA5 belong to the family of cell division cycle related genes. Studies have shown that miR-133a-3p can target CDCA8 and inhibit the progress of ESCA [35]. TPX2 can enhance the expression of cyclin-dependent kinase-1 (CDK1) in PRAD, then promote the phosphorylation of the ERK/GSK3b/Snail pathway, and finally EMT[36]. Kinesin family protein 2C (KIF2C), also known as mitotic centromere-associated driving protein, encodes proteins in microtubule depolymerization, thus promoting chromosome separation during mitosis. KIF2C is highly expressed in HCC, related to tumor histological grade, pathological stage, and poor prognosis. In addition, KIF2C can promote the progression of HCC by activating the renin-angiotensin system (RAS)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways [37]. Kinesin family member 23 (KIF23) is a member of the Kinesin family, highly expressed in triple-negative breast cancer (TNBC). Silencing of KIF23 expression can inhibit the proliferation and migration of the TNBC cells [38]. Recent research has demonstrated that KIF4A expression is up-regulated in LUAD and correlates with the prognosis of the patients [39]. Additionally, it has been reported that miR-877-5p could inhibit cell growth by directly targeting FOXM1, potentially furnishing a promising biomarker for targeted therapy in NSCLC [40]. MCM7 belongs to the small chromosome maintenance protein family, with a pivotal role in DNA replication and proliferation in eukaryotic cells. Several studies indicated that receptor for activated C kinase1 (RACK1) could modulate the growth and cell cycle progression of human NSCLC cells through MCM7 phosphorylation mediated by the MCM7/RACK1/Akt signal complex [41]. CDCA5 plays an important role in the occurrence and development of many kinds of cancers by regulating cell cycle. CDCA5 is highly expressed in breast cancer tissues and cell lines. CDCA5 deletion can inhibit cell proliferation, invasion, and migration. Hence, CDCA5 can be used as a prognostic biomarker and therapeutic target for breast cancer [42]. Thus, the above YKT6-related hub genes are all correlated to tumor progression and prognosis, with functions on tumor cell proliferation, invasion or migration.
Enrichment analysis of YKT6 and its related genes showed the main physiological functions were cell division, mitosis, and the cell cycle. Consistently, the hub genes screened were mainly cell cycle-related. YKT6 may play a role in LUAD through PLK1 and TP53 pathways as demonstrated by GSEA. In addition, it is mentioned above that PLK1 can promote the progress of LUAD with K-ras/TP53 mutation by regulating the transcriptional activation receptor RET. Thus, there may exist certain relationship between YKT6 and PLK1 in the occurrence and development of LUAD, which needs further verification.
In recent years, tumor immune escape has been the focus of anti-tumor therapy. Numerous immune cells including macrophage, T cell, and NK cell constitute the tumor microenvironment. These cells directly or indirectly affect the microenvironment of tumor cells and regulate their biological behaviors. Therefore, immune cell therapy has a broad application prospect in the treatment of LUAD. YKT6 is related to immune cell infiltration in LUAD (data not shown). The increased infiltration of immune cells is accompanied by elevated YKT6 expression, providing the foundation for effective immunotherapy. Thus, the findings have provided novel insights into immunotherapy for patients with LUAD.
To sum up, our present study shows that YKT6 is supported as a potential new biomarker of LUAD. However, it is not clear how YKT6 regulates the occurrence and development of LUAD. Further research and clinical verification are needed to explore the underlying molecular mechanism of YKT6 in the initiation and treatment of LUAD.