NKX6-1 mediates cancer stem-like properties and regulates sonic hedgehog signaling in leiomyosarcoma

Abstract

Background Leiomyosarcoma (LMS), the most common soft tissue sarcoma, exhibits heterogeneous and complex genetic karyotypes with severe chromosomal instability and rearrangement and poor prognosis. Methods Clinical variables associated with NKX6-1 were obtained from The Cancer Genome Atlas (TCGA). NKX6-1 mRNA expression was examined in 49 human uterine tissues. The in vitro effects of NXK6-1 in LMS cells were determined by reverse transcriptase PCR, western blotting, colony formation, spheroid formation, and cell viability assays. In vivo tumor growth was evaluated in nude mice. Results Using The Cancer Genome Atlas (TCGA) and human uterine tissue datasets, we observed that NKX6-1 expression was associated with poor prognosis and malignant potential in LMS. NKX6-1 enhanced in vitro tumor cell aggressiveness via upregulation of cell proliferation and anchorage-independent growth and promoted in vivo tumor growth. Moreover, overexpression and knockdown of NKX6-1 were associated with upregulation and downregulation, respectively, of stem cell transcription factors, including KLF8, MYC, and CD49F, and affected sphere formation, chemoresistance, NOTCH signaling and Sonic hedgehog (SHH) pathways in human sarcoma cells. Importantly, treatment with an SHH inhibitor (RU-SKI 43) but not a NOTCH inhibitor (DAPT) reduced cell survival in NKX6-1-expressing cancer cells, indicating that an SHH inhibitor could be useful in treating LMS. Finally, using the TCGA dataset, we demonstrated that LMS patients with high expression of NKX6-1 and HHAT, an SHH pathway acyltransferase, had poorer survival outcomes compared to those without. Conclusions Our findings indicate that NKX6-1 and HHAT play critical roles in the pathogenesis of LMS and could be promising diagnostic and therapeutic targets for LMS patients.

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

“…Despite all these frustrating facts, studies still prove the antitumor effects of SHH inhibitors in PDAC. RU-SKI 43, an HHAT inhibitor, was reported to hinder PC cell growth via smoothing-independent non-canonical signaling and could potentially treat leiomyosarcoma, according to Ph, S., and colleagues [328,329]. Moreover, combination therapies have exhibited some promising results.…”

Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock

“…MEF2C has reported roles in numerous age-related conditions, including Alzheimer’s disease ( Xue et al, 2021 ) and muscle wasting in cancer ( Judge et al, 2020 ) and GRM is associated with age-related hearing loss ( Liu et al, 2021b ). Additional candidates are reported to be involved in cancer prognosis and progression, including TSPAN11 ( Liu et al, 2021a ), NKX6-1 ( Su et al, 2021 ), and SLC16A1 ( Zhang et al, 2021 ).…”

Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock

“…26 MEF2C has reported roles in numerous age-related conditions, including Alzheimer’s disease 27 and muscle wasting in cancer 28 and GRM is associated with age-related hearing loss. 29 Additional candidates are reported to be involved in cancer prognosis and progression, including TSPAN11 , 30 NKX6-1 , 31 and SLC16A1 . 32…”

“…26 MEF2C has reported roles in numerous age-related conditions, including Alzheimer's disease 27 and muscle wasting in cancer 28 and GRM is associated with age-related hearing loss. 29 Additional candidates are reported to be involved in cancer prognosis and progression, including TSPAN11, 30 NKX6-1, 31 and SLC16A1. 32 Gene enrichment analysis 33 identified significant associations (adjusted p < 0.05) between our gene candidates and macular thickness and degeneration, as seen in previous human GWAS studies 34 and cataract formation (Elsevier pathway collection), 35 as well as non-eye related diseases such as bone mineralization, tumor suppression, and Amyloid Precursor Protein pathways (Biocarta).…”