Cholesterol import and steroidogenesis are biosignatures for gastric cancer patient survival

Abstract

Androgens, estrogens, progesterone and related signals are reported to be involved in the pathology of gastric cancer. However, varied conclusions exist based on serum hormone levels, receptor expressions, and in vitro or in vivo studies. This report used a web-based gene survival analyzer to evaluate biochemical processes, including cholesterol importing via lipoprotein/receptors (L/R route), steroidogenic enzymes, and steroid receptors, in gastric cancer patients prognosis. The sex hormone receptors (androgen receptor, progesterone receptor, and estrogen receptor ESR1 or ESR2), L/R route (low/high-density lipoprotein receptors, LDLR/LRP6/SR-B1 and lipoprotein lipase, LPL) and steroidogenic enzymes (CYP11A1, HSD3B1, CYP17, HSD17B1, HSD3B1, CYP19A1 and SRD5A1) were associated with 5-year survival of gastric cancer patients. The AR, PR, ESR1 and ESR2 are progression promoters, as are the L/R route LDLR, LRP6, SR-B1 and LPL. It was found that CYP11A1, HSD3B1, CYP17, HSD17B1 and CYP19A1 promote progression, but dihydrotestosterone (DHT) converting enzyme SRD5A1 suppresses progression. Analyzing steroidogenic lipidome with a hazard ratio score algorithm found that CYP19A1 is the progression confounder in surgery, HER2 positive or negative patients. Finally, in the other patient cohort from TCGA, CYP19A1 was expressed higher in the tumor compared to that in normal counterparts, and also promoted progression. Lastly, exemestrane (type II aromatase inhibitor) dramatically suppress GCa cell growth in pharmacological tolerable doses in vitro. This work depicts a route-specific outside-in delivery of cholesterol to promote disease progression, implicating a host-to-tumor macroenvironmental regulation. The result indicating lipoprotein-mediated cholesterol entry and steroidogenesis are GCa progression biosignatures. And the exemestrane clinical trial in GCa patients of unmet medical needs is suggested.

Mitochondrial Acetyl‐CoA Synthetase 3 is Biosignature of Gastric Cancer Progression

“…In summary, our study showed that cholesterol supply promotes GCa progression , while de novo cholesterol synthesis is irrelevant to GCa progression. These results are consistent with those of Yorket al (2015), who found that cholesterol influx is reduced by activating type I IFN signaling in cancer .…”

“…In previous work, we developed a formula to calculate the impact of genes on different GCa conditions with the KM plotter survival analyzer :…”

“…Cholesterol is a major component of cell membranes and a vital metabolic material for fast‐growing cancer cells. A previous study has shown the importance of low‐density lipoprotein (LDL) and its cholesterol‐shuttling receptor (LDLR; L/R route), which facilitate steroidogenesis and sex hormone receptor action, and promote GCa progression . The study indicated that the L/R route is a GCa progression biomarker.…”

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…The following formula was used to calculate HR scores20: $\begin{array}{cc}\hfill \text{HR score}=& \text{Avg. HR score of gene sets}=\hfill \\ & \frac{\sum false({\text{HR}}_{\mathrm{n}}-1false)\times false(-{\text{log}}_{10}(P\text{value})false)}{\mathrm{normaln}}\times 100\hfill \end{array}$ …”

“…There are online databases to validate the importance of gene expressions in BCA patient survival (http://kmplot.com/analysis/index.php?p=service&cancer=breast). Beneficiary from the advances of bioinformatics, using the web‐based genome‐scale gene expression survival analyzer followed with pathway weighting algorithm, we are able to evaluate gene clusters/pathways‐of‐genes in cancer patient prognosis in a hypothesis‐driven basis 20. To test our hypothesis, we performed Kaplan Meier plotter to investigate the role of S1P in BCA patient survival (http://kmplot.com/analysis/index.php?p=service&cancer=breast) and the association between S1P metabolism and BCA progression.…”