Integrated multi-dimensional analysis highlights DHCR7 mutations involving in cholesterol biosynthesis and contributing therapy of gastric cancer

Abstract

Background Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. Methods A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. Results At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. Conclusion In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.

TMEM147 aggravates the progression of HCC by modulating cholesterol homeostasis, suppressing ferroptosis, and promoting the M2 polarization of tumor-associated macrophages

“…Our results were similar to those in HeLa cells, and we explored the potential underlying mechanisms. DHCR7 has crucial functions in several malignant diseases such as gastric cancer [ 13 ] and colorectal cancer. [ 14 ] In this study, we found that the positive effect of TMEM147 on the proliferation, invasion, and migration of HCC cells mainly relies on DHCR7, which is related to the DHCR7-modulated cholesterol ester metabolism.…”

ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis

“…Transwell migration and invasion experiments were conducted using the approach described in our previous study 17 . In the migration assay, a total of 3 × 10 4 GC cells were seeded in the upper compartments of a 24‐well plate (Corning, NY, USA, #353097) with an 8 μm pore size membrane.…”

“…Transwell migration and invasion experiments were conducted using the approach described in our previous study. 17 In the migration assay, a total of 3 × 10 4 GC cells were seeded in the upper compartments of a 24-well plate (Corning, NY, USA, #353097) with an 8 μm pore size membrane. The upper compartments were filled with 400 μL of serum-free media, while the bottom compartments were filled with 400 μL of media containing 20% FBS.…”

Identification and validation of DHCR7 as a diagnostic biomarker involved in the proliferation and mitochondrial function of breast cancer

“…DHCR7 is already recognized as a risk factor in several tumors via regulating circulating vitamin D concentration, including ovarian cancer [ 18 ], nonmelanoma skin cancer [ 19 ], and thyroid cancer [ 20 ]. In addition, DHCR7 has been shown to be an oncogene and its high expression regulates the proliferation, migration, and invasion as well as apoptosis of tumor cells, such as in bladder cancer [ 21 ] and gastric cancer [ 22 ]. Additionally, DHCR7 is a vitamin D-related gene that interacts with 25(OH)D to increase the risk of BC [ 23 ].…”