Evidence for an oncogenic role of HOXC6 in human non-small cell lung cancer

Abstract

Background Identification of specific biomarkers is important for the diagnosis and treatment of non-small cell lung cancer (NSCLC). HOXC6 is a homeodomain-containing transcription factor that is highly expressed in several human cancers; however, its role in NSCLC remains unknown. Methods The expression and protein levels of HOXC6 were assessed in NSCLC tissue samples by Quantitative real-time PCR (qRT-PCR) and immunohistochemistry, respectively. HOXC6 was transfected into the NSCLC cell lines A549 and PC9, and used to investigate its effect on proliferation, migration, and invasion using CFSE, wound healing, and Matrigel invasion assays. Next-generation sequencing was also used to identify downstream targets of HOXC6 and to gain insights into the molecular mechanisms underlying its biological function. Results HOXC6 expression was significantly increased in 66.6% (20/30) of NSCLC tumor samples in comparison to normal controls. HOXC6 promoted proliferation, migration, and invasion of NSCLC cells in vitro. RNA-seq analysis demonstrated the upregulation of 310 and 112 genes in A549-HOXC6 and PC9-HOXC6 cells, respectively, and the downregulation of 665 and 385 genes in A549-HOXC6 and PC9-HOXC6 cells, respectively. HOXC6 was also found to regulate the expression of genes such as CEACAM6, SPARC, WNT6, CST1, MMP2, and KRT13, which have documented pro-tumorigenic functions. Discussion HOXC6 is highly expressed in NSCLC, and it may enhance lung cancer progression by regulating the expression of pro-tumorigenic genes involved in proliferation, migration, and invasion. Our study highlighted the oncogenic potential of HOXC6, and suggests that it may be a novel biomarker for the diagnosis and treatment of NSCLC.

The vascular nature of lung-resident mesenchymal stem cells

“…Likewise, the oncogenic potential of HOXC6 was investigated. HOXC6 expression was significantly increased in the majority of NSCLC tumor samples in as compared to healthy control lungs, which suggested HOXC6 as a novel biomarker for the diagnosis and treatment of NSCLC 63 . Accordingly, ectopic expression of HOXC6 in NSCLC cell lines promoted proliferation, migration, and invasion of respective NSCLC cells 63 .…”

“…HOXC6 expression was significantly increased in the majority of NSCLC tumor samples in as compared to healthy control lungs, which suggested HOXC6 as a novel biomarker for the diagnosis and treatment of NSCLC. 63 Accordingly, ectopic expression of HOXC6 in NSCLC cell lines promoted proliferation, migration, and invasion of respective NSCLC cells. 63 From the three MSC-specific HOX candidates, HOXC8 was also found to be upregulated in clinical NSCLC specimens, and the high expression of HOXC8 correlated with tumor grade, tumor node metastasis stage, and poor relapse-free survival for lung cancer patients.…”

“…63 Accordingly, ectopic expression of HOXC6 in NSCLC cell lines promoted proliferation, migration, and invasion of respective NSCLC cells. 63 From the three MSC-specific HOX candidates, HOXC8 was also found to be upregulated in clinical NSCLC specimens, and the high expression of HOXC8 correlated with tumor grade, tumor node metastasis stage, and poor relapse-free survival for lung cancer patients. 64 Mechanistically, HOXC8 functioned as a transcriptional activator of transforming growth-factor beta signaling pathway, finally mediating increased proliferation, anchorage-independent growth and migration of NSCLC, as well as chemoresistance and antiapoptosis in NSCLC.…”

HomeoboxC6 affects the apoptosis of human vascular endothelial cells and is involved in atherosclerosis

“…Specific transcription factors, for example, HOXC6, act as either activators or inhibitors to modulate numerous target genes, thereby determining cell fate. In recent years, studies have demonstrated that HOXC6 is highly expressed in multiple types of cancer, and influenced the malignant biological behavior of cancer cells (Fujiki et al, 2008; Ramachandran et al, 2005; Sulkava et al, 2017; X. Wang, Chen et al, 2019; Y.Wang, Wang, et al, 2019; Yang et al, 2019). Other studies also found that there were lower expression levels of HOXC6 in ascending aortic aneurysm and carotid atheromatous plaque (Huang et al, 2016; Sulkava et al, 2017).…”

Lung-Resident Mesenchymal Stem Cell Fates within Lung Cancer

“…As the most originating sites of the different lung cancer types were correlated with the areas of distinct epithelial cells and their progenitor cells, even LR-MSCs could hypothetically lead to de-differentiation of lung stem cells, thereby initiating lung cancer; or at least differentiate into (divers) non-tumorigenic stromal cells that ultimately define the histological type of NSCLC [ 12 , 16 , 33 ]. Conformingly, MSC-related marker expressions (e.g., CD90, CD44, CD105, CD73 as well as LR-MSC specific HOX transcription factors) were associated with low pathologic stage in NSCLC and/or accounted for a reduced overall survival of respective patients [ 47 , 48 , 49 , 50 ]. Elevated MSC marker particularly in malignant lung epithelial cells could indicate that NSCLC may at least partially derive from LR-MSCs [ 33 , 47 , 48 , 49 , 50 ].…”