With the rapid development of biotechnology, metabolic reprogramming is no longer limited to alterations in glycolysis and the tricarboxylic acid cycle but is further extended to fatty acid metabolism, glutamine metabolism, and serine metabolism. Some studies have shown that metabolic reprogramming not only affects the biosynthesis and energy metabolism of tumor cells but also exerts regulatory effects on the immune response process through various metabolic enzymes and metabolic molecules, ultimately influencing tumor development and progression[23, 24]. Sugar and glutamine are the main sources of energy for the rapid proliferation of ovarian cancer cells. Hyperglycemia, as a presenting feature of overweight and obesity, is associated with tumorigenesis and poor prognosis, and may increase the risk of OC. In terms of glutamine metabolism, highly invasive ovarian cancer cells were significantly dependent on glutamine, and high expression of glutamine synthetase is associated with poor prognosis in OC patients[26, 27]. Thus, tumor metabolism is not only associated with the development of OC, but also affects patient prognosis. However, an effective prognostic signature for OC based on metabolism-related genes is still lacking.
In this study, a prognostic signature consisting of 21 metabolic genes was developed based on the training set from TCGA and GTEx, and validated in an independent external dataset from GEO. The results showed a poor prognosis for OC patients with higher risk scores. Moreover, the results of univariate and multivariate Cox regression indicated that this prognostic signature could be used as an independent prognostic factor for OS. As expected, the differentially expressed metabolic genes were mainly enriched in functions associated with metabolism, including oxidative phosphorylation, cytochrome P450 enzyme exogenous substance metabolism, cytochrome P450 enzyme drug metabolism, and purine metabolism, reflecting potential molecular mechanisms of dysregulated genes in the metabolic microenvironment of OC. In addition, there was a significant difference in terms of immune cell infiltration, immune score, and stromal score between the high- and low-risk groups.
Most of the 21 metabolic genes in the signature have been reported to be associated with malignancy. Previous studies have reported that up-regulated expression of Agpat4 in colorectal cancer (CRC) tissues is strongly associated with poor prognosis. ALDH1L1, a candidate tumor suppressor, is often silenced in tumor tissues and is positively correlated with tumorigenesis and invasiveness. The glycosylation enzymes CSGALNACT1, GALNT10 and GFPT2 were overexpressed in prostate cancer, high grade ovarian serous cancer (HGSC) and lung adenocarcinoma, respectively. They were also found to play a key role in various biological processes in tumorigenesis, including immune surveillance and cell metabolism[30–32]. CYP2S1 has been reported to be largely associated with cell proliferation and lipid metabolism, and the downregulation of CYP2S1 was reported to promote proliferation of CRC cells. Inhibition of DGKD expression reduces the proliferation of castration-resistant and androgen-dependent prostate cancer cells. DHRS9 expression is reduced in oral squamous cell carcinoma tissues, and low expression of DHRS9 is strongly associated with tumor progression and poor prognosis. Significant upregulation of LYPLA1 was observed in non-small cell lung cancer (NSCLC) cells in vitro, which is found to be pro-tumorigenic. PDE7B can degrade intracellular cAMP, which inhibits cell cycle arrest and apoptosis of cancer cells. At present, elevated expression of PDE7B has been detected in various malignant tumors, and it negatively impacts survival. PRPS2 promotes nucleotide biosynthesis, which drives cancer initiation and progression. Another study confirmed that PRPS2 is significantly up-regulated in prostate adenocarcinoma and is strongly associated with progression. As for UGT2B15 and UQCRFS1, they were involved in glucuronidation and electron transfer in the mitochondrial respiratory chain, respectively. Both were found overexpressed in gastric cancer, with overexpression of UGT2B15 negatively correlated with the prognosis[39, 40]. MIF, PDE10A, PLA2G2D, and WARS are primarily involved in immunomodulation and inflammatory response[41–44].
To further uncover the biological implications of the prognostic genes in the signature, we explored gene mutation and tumor microenvironment of the two groups. Genetic alterations were found in all these prognostic metabolic genes in OC, with amplification being the most common type. Missense mutation is the most common in both the high- and low-risk groups. It has been previously reported that an increase, decrease in genomic copy number, or other mutations could result in alterations in gene expression . These alterations may be the potential mechanism for dysregulated expression of 21 metabolic genes in the prognostic signature. As for the drug sensitivity analysis, the results indicated that DCT, DGKD and TPMT could be potential biomarkers for drug screening.
The results of immune cell infiltration indicated that there are a variety of immune cells that are significantly different between the high- and low-risk groups, and the immune score of the high-risk group is lower than the low-risk group. It has been confirmed that the higher metabolic activity greatly impacts the nutrient composition of the tumor microenvironment, which may have a critical impact on the local immune response. There is growing evidence that the metabolism and function of T cells are restricted by dysregulated glycolysis in tumor tissues, thereby impairing the immune response[47, 48]. For example, the expression of tumor-associated glycolysis-related genes was negatively correlated with T-cell infiltration in melanoma and NSCLC patients compared to controls . Recent studies have reported that, compared with healthy controls, Teff cells from cancer patients show reduced activity and dysfunction of mitochondria, thus failing to achieve substantial cell division and anti-tumor immune effects. This is consistent with our findings that Tregs infiltration was less common in the high-risk group than the low-risk group. Meanwhile, pieces of evidence suggest that tumor growth is promoted by itaconic acid-mediated immunomodulation. Metabolomics revealed that immune-responsive gene 1 (IRG1) modulated immune response by catalyzing the production of itaconic acid, directly linking metabolism to immunity . Weiss et al verified that itaconic acid promotes fatty acid oxidation-mediated oxidative phosphorylation and glycolysis, by up-regulating macrophages in ovarian cancer tissues. In addition, the expression of IRG1 was significantly elevated in monocytes from OC patients. Consistently, our study observed different infiltration patterns of monocytes and macrophages between two groups, implying potential roles of these cells in tumorigenesis. Overall, these studies reveal that the metabolic reprogramming in cancer patients has a pivotal impact on the local and systemic immune response, which is closely related to tumor progression and patient prognosis.
Admittedly, there are still some limitations to the study. First, since additional clinical information, such as metabolic disorders and therapies, cannot be obtained from the databases, we were unable to assess the association between our model and these aspects. Second, the patients from different databases had diverse ethnic and cultural backgrounds. Thus, we should be cautious when applying the model in a certain population and more independent cohort studies are needed to validate the signature. Also, more basic research is needed to clarify the specific roles of metabolic genes in the pathogenesis and progression of OC.