The HMGCS2-associated hub genes as promising targets for ulcerative colitis patients

doi:10.21203/rs.3.rs-4699422/v1

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The HMGCS2-associated hub genes as promising targets for ulcerative colitis patients

https://doi.org/10.21203/rs.3.rs-4699422/v1

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Ulcerative colitis (UC) is a chronic inflammatory disease of colon with unclear pathogenesis. Studies have shown that 3-hydroxy-3-methylglutaryl-CoAsynthase 2 (HMGCS2) may play an important role in inflammation, but its role in UC especially those in remission phase has not been investigated. The transcriptional profile of normal and UC patients was extracted from the Gene Expression Omnibus database (GEO), and the results revealed that HMGCS2 was significantly downregulated in both inflamed and remission samples of UC patients as compared to controls. We generated Caco-2 and HT-29 cells lacking HMGCS2 by lentivirus shRNA vectors. The analysis of RNA-seq data of the cells showed that knockdown of HMGCS2 significantly downregulated fatty acid (FA)-metabolism pathway by KEGG analysis, and HMGCS2-associated FA-metabolism-related hub genes (Hub^HMGCS2−FA) were retrieved. Further validation in GEO datasets showed that the Hub^HMGCS2−FA panel were significantly correlated with FA-metabolism pathway. The risk score model^HMGCS2−FA was then established, and its prediction effect in distinguishing UC patients in active as well as remission phase from normal controls is good (AUC:0.85-1). Therefore, HMGCS2 plays an important role in patients with UC in not only active but also remission phase and may serve as promising biomarkers and therapeutic targets in the future.

ulcerative colitis

HMGCS2

fatty acid metabolism

remission

risk score

Ulcerative colitis (UC) is an inflammatory disease characterized by recurrent episodes of diarrhea, mucopurulent and bloody stools, and abdominal pain(Lasa et al., 2022). The course of UC often alternates between active phase and remission phase, which greatly reduces the quality of life for UC patients and brings a huge physical and economic burden to patients(Keefer et al., 2022; Yang et al., 2022). In recent years, the management goal of UC has evolved from the previous singular focus on inducing clinical remission to a gradual shift towards assessing and inducing fully sustained remission in patients to prevent another episode of the disease and reduce hospitalizations and surgeries(Le Berre & Peyrin-Biroulet, 2021; Pineton de Chambrun et al., 2010). However, there is still a lack of effective and accurate biomarkers to help us define and predict the remission phase. Therefore, it is necessary to standardize the assessment of remission period, search for new core genes related to UC and delve deeper into its pathogenic mechanisms.

The 3-hydroxy-3-methylglutaryl-CoAsynthase 2 (HMGCS2) is a key enzyme in ketone body generation, mainly expressed in highly differentiated regions of the intestinal mucosa(Kim et al., 2019). In a study of colon cancer, it was found that inhibition of HMGCS2 increased glycolysis and decreased fatty acid β-oxidation in colon cancer cells(Kim et al., 2023). In a previous integrated bioinformatics analysis study, HMGCS2 was found to be a relevant gene in the development of UC, which may be associated with the infiltration of neutrophils, monocytes and macrophages(Li et al., 2022; Zhao et al., 2023). Compared with normal tissues, HMGCS2 expression level was inhibited in the intestinal epithelium of UC patients in active phase(Kim et al., 2021), but its role in remission phase has not been studied. HMGCS2-associated genes may be valuable research targets for UC, and prediction models established based on their expression may predict UC patients in active phase or even remission phase from healthy controls. However, studies of HMGCS2 in remission samples of UC patients and HMGCS2-asssociated prediction models are scarce.

In our current study, we retrieved the expression level of HMGCS2 in inflamed and remission samples of UC patients from GEO datasets using bioinformatics analysis. To investigate the role of HMGCS2 in epithelial cells, we knocked down HMGCS2 in Caco-2 and HT-29 cells using lentivirus shRNA vectors. The RNA of Caco-2 and HT-29 cells lacking HMGCS2 was then extracted and subjected to RNA sequencing analysis. Differentially expressed genes (DEGs) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed to retrieve HMGCS2-associated fatty acid (FA) metabolism-related hub genes (Hub^HMGCS2−FA). We then established risk score model^HMGCS2−FA to predict UC patients using GEO datasets. Our study indicates a novel protective role of HMGCS2-associated hub genes in regulating epithelial cell injury of UC patients in not only active phase but also in remission phase.

Cell culture and transfection

The human colon cancer cell lines Caco-2 and HT-29 were purchased from Procell Life Technology Co., Ltd (Wuhan, China) and cultured in Dulbecco's Modified Eagle Medium (DMEM) and McCoy's 5A supplemented with 10% fetal bovine serum and 1% streptomycin, respectively. Cells were further cultured at 37 ℃ in a humidified incubator containing 5% CO2. The HMGCS2 knockdown lentiviral vector was obtained from Genechem Co., Ltd (Shanghai, China). Following the manufacturer's instructions, Caco-2 and HT29 cells were infected with the HMGCS2 knockdown lentiviral vector, and stable cell lines were obtained through selection with puromycin (Solarbio Technology Co., Ltd. Beijing, China).

Western Blot Analysis

Total protein from cultured cells was isolated in lysis buffer supplemented with protease and phosphatase inhibitors. Protein concentration was measured by BCA method (Solarbio Technology Co., Ltd. Beijing, China). And the amount of protein in all samples was normalized to 30 µg. The samples were electrophoresed by SDS-PAGE and transferred to PVDF membranes, which were blocked with 5% skim milk for 1.5h at room temperature and then incubated with HMGCS2 antibodies (1:1000) overnight at 4℃. After washing with TBST, secondary antibodies (1:5000) were incubated for 1.5h at room temperature. The bands were visualized using enhanced chemiluminescence (ECL) detection reagents. The HMGCS2 antibody used in this study was purchased from Abcam (Cambridge, MA, USA). GAPDH antibody were obtained from HuaAn Biotechnology Co., Ltd (Hangzhou, China).

Total RNA extraction

Total RNA was isolated from Caco-2 and HT-29 cells before and after HMGCS2 knockdown and extracted using a total RNA extraction kit (Vazyme) according to the manufacturer's instructions. RNA concentration and purity were analyzed using a NanoDrop2000 spectrophotometer (Themo Scientifc), RNA integrity was determined by agarose gel electrophoresis, and RIN values were determined using an Agilent 2100 bioanalyzer. Total RNA samples were used for RNA sequencing, and a single library was required to have a total amount of RNA ≥ 1ug, concentration ≥ 35 ng/µL, OD260/280 ≥ 1.8, OD260/230 ≥ 1.0.

RNA sequencing

The RNA sequencing was performed by Meiji Biotech (Shanghai, China). Eukaryotic mRNA has the structure of ploy A tail at the 3 'end, using magnetic beads with Oligo (dT) for A-T base pairing with ploy A, mRNA can be isolated from total RNA. With the addition of fragmentation buffer and small fragments of about 300bp can be separated by magnetic bead screening. Under the action of reverse transcriptase, random hexamers were added, and mRNA was used as a template to reverse synthesize one-strand cDNA, followed by two-strand synthesis to form a stable double-stranded structure. The products after adapter ligation were purified and fragment sorted, and the sorted products were used for PCR amplification and purification to obtain the final library. Qubit 4.0 was quantified, mixed in proportion to the data, and bridge-PCR was performed on the cBot to generate clusters, which were sequenced on the Illumina Nova Seq 6000 platform (PE library, 2×150bp read length).

RNA Sequencing Data Analysis

The DEGs between the control group and the HMGCS2 knockdown group were screened using DESeq2 (http://bioconductor.org/packages/stats/bioc/DESeq2) in R software with the screening criteria being P < 0.05, and the volcano plot was drawn. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed using the R-based fgsea package, with a cut-off threshold of p-value < 0.05 used for selection.

Screening Gene Chip datasets

The GEO database (https://www.ncbi.nlm.nih.gov/gds/) is one of the largest public gene chip databases in the world. A search was conducted using the keywords "ulcerative colitis", "human", "active" and "remission". Eventually, datasets GSE38713 and GSE59071 from the GEO library were included in the analysis.

Establishment of risk score-related prediction model

To verify whether HMGCS2-associated genes could distinguish between UC patients in active or remission phase and normal controls, we established a risk score-related prediction model based on these genes. The formula for risk score is(Feng et al., 2020):

Risk Score=

(n: the count of genes; wi: the weight value of the ith gene; ei: the expression level of the ith gene; ui: mean value for the ith gene among whole samples; si: standard deviation value for the ith gene among whole samples.)

The ROC curves were generated using the R software package and the area under the curve (AUC) was calculated to assess diagnostic accuracy.

Statistical analyses

R software (version 4.3.1) was used for statistical analysis, and the measurement data were expressed as‾x ± s. Statistical comparisons were made using one-way ANOVA to test the differences between multiple groups of data, and comparisons between two groups were made using the two independent samples t-test, with differences considered statistically significant at P < 0.05.

The expression of HMGCS2 is repressed in not only inflamed tissues but also remission tissues from patients with UC

Previous study indicated that HMGCS2 repression takes place in inflamed tissues from UC patients(Martín-Adrados et al., 2023). However, few studies focused on the expression of HMGCS2 in UC patients with remission phase. Here, the microarray data analysis of GSE38713 and GSE59071 datasets showed that the expression of HMGCS2 was downregulated in inflamed as well as remission tissues of UC patients (Fig. 1A and B), suggesting that although UC patients have been clinically diagnosed as in remission phase, persistent mucosal damage remains uncorrected.

HMGCS2 knockdown downregulated fatty acid metabolism pathway and its leading edges

Intestinal epithelial cells provide the first line of defense in the colonic mucosa. There is evidence showing that HMGCS2 knockdown induced endoplasmic reticulum stress in Caco-2 cells(Martín-Adrados et al., 2023). To determine whether HMGCS2 is significant for epithelial cell damage, we generated Caco-2 and HT-29 cells lacking HMGCS2 by lentivirus infection. Western blot analysis validated efficient reduction of HMGCS2 protein level in Caco-2 and HT-29 cells (Fig. 1C and D), indicating the successful establishment of HMGCS2 knockdown cell lines. The RNA of Caco-2 and HT-29 cells lacking HMGCS2 was then extracted and subjected to RNA sequencing analysis. Differentially expressed genes (DEGs) analysis in each group were performed by applying the criteria p-value < 0.05 using DESeq2 package in R software. Volcano maps in Fig. 1E visualized DEGs in Caco-2 and HT-29 cells with HMGCS2 knockdown as compared to control groups. A total of 559 DEGs (199 down-regulated and 360 up-regulated) and 11030 DEGs (5357 down-regulated and 5673 up-regulated) DEGs were identified in Caco-2 and HT-29 cells with HMGCS2 knockdown, respectively.

To reveal the pathway dysregulation affected by HMGCS2 knockdown of Caco-2 and HT-29 cells, we employed the R-based fgsea package for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. All the significant KEGG pathways affected in Caco-2 and HT-29 cells were selected using a cut-off threshold of p-value < 0.05 (Fig. 1F). The results showed that cytokine cytokine receptor interaction pathway was upregulated in both Caco-2 and HT-29 cells after KEGG knockdown. More interestingly, fatty acid metabolism pathway was significantly downregulated in both cell lines (Fig. 1G), indicating that HMGCS2 might play a critical role in the damage of epithelial cells via influencing the fatty acid metabolism pathway.

The Hub ^HMGCS2−FA gene panel was established in vitro and was validated in human data.

Encouraged by above findings, we further identified potential hub genes for epithelial cell damage associated with HMGCS2 within the leading-edge genes from fatty acid metabolism pathway (Fig. 2A, heatmap). By overlapping the leading-edge genes between Caco-2 and HT-29 cells, we identified 10 candidate genes associated with HMGCS2 (Hub^HMGCS2−FA) (Fig. 2A). To further investigate the role of the Hub^HMGCS2−FA gene panel in UC patients, we analyzed the gene expression pattern as well as the alteration of fatty acid metabolism pathway in GSE38713 and GSE59071 datasets.

The dataset GSE38713 comprises a total of 36 colonic mucosal samples, including 15 samples from the inflamed regions during the active phase of UC, 8 samples from the remission phase of UC and 13 samples from healthy controls. The gene expression level of Hub^HMGCS2−FA panel was shown in Fig. 2B. KEGG pathway analysis using fgsea package in R software revealed that fatty acid metabolism pathway was significantly downregulated in not only the inflamed tissues (Fig. 2C) but also the remission tissues (Fig. 2D) of UC patients in GSE38713. GSVA analysis was also performed to estimate fatty acid metabolism pathway of every single sample of UC patients. Then, we created a correlation heatmap using the corrplot package to display the connections between the ten genes of Hub^HMGCS2−FA panel and the fatty acid metabolism pathway, and the correlation strength was indicated as a score. The results showed that HMGCS2 was positively correlated with fatty acid metabolism pathway and multiple pairs of genes from Hub^HMGCS2−FA panel in inflamed tissues of UC patients (Fig. 2E). What`s more, the expression of HMGCS2 in remission tissues was also significantly positively correlated with fatty acid metabolism pathway and multiple pairs of genes from Hub^HMGCS2−FA panel (Fig. 2F).

We then included dataset GSE59071 to validate the above observations. GSE59071 comprises a total of 108 samples with 74 samples from inflamed regions during the active phase of UC, 23 samples from the remission phase of UC and 11 samples from healthy controls. The gene expression level of Hub^HMGCS2−FA panel was shown in Fig. 3A. KEGG pathway analysis revealed that fatty acid metabolism pathway was significantly downregulated in not only the inflamed tissues (Fig. 3B) but also the remission tissues (Fig. 3C) of UC patients in GSE59071. The correlation heatmap showed that HMGCS2 was also positively correlated with fatty acid metabolism pathway and multiple pairs of genes from Hub^HMGCS2−FA panel in inflamed tissues of UC patients in GSE59071 (Fig. 3D). Also, the expression of HMGCS2 in remission tissues was significantly positively correlated with fatty acid metabolism pathway and multiple pairs of genes from Hub^HMGCS2−FA panel in GSE59071 (Fig. 2E).

The risk score model ^HMGCS2−FA showed good performance in predicting UC patients in remission phase from healthy controls.

We established a predictive model with a scoring system that represents the linear combination gene expression values of the Hub^HMGCS2−FA panel, named risk score model^HMGCS2−FA. The assessment of performance metrics for the risk score model^HMGCS2−FA revealed significantly higher risk for UC patients in not only active phase but also remission phase as compared to that from healthy individuals in both GSE38713 and GSE59071 datasets (Fig. 3F). These data indicated that during the remission phase, UC patients might still have persistent colonic injury and have not achieved fully healing. The specificity and sensitivity of risk score model^HMGCS2−FA in predicting UC patients were verified using ROC curve analysis, demonstrating unbiased prediction of UC patients in active phase as well as remission phase in the microarray datasets using the Hub^HMGCS2−FA-guided machine learning bioinformatic approach. Based on the risk score model^HMGCS2−FA analysis, the AUC values were 1 and 0.99 for the inflamed tissues from UC as compared to controls in GSE38713 and GSE59071, respectively (data was not shown). More interestingly, the AUC values were 1 and 0.85 in remission tissues of UC patients as compared to controls in GSE38713 and GSE59071, respectively (Fig. 3G). These results collectively indicate that the risk score model^HMGCS2−FA can be used for the prediction of UC in not only active phase but also remission phase from healthy controls. The Hub^HMGCS2−FA gene panel could be a potential biomarker or therapeutic target for ulcerative colitis patients in active phase or even remission phase.

Ulcerative colitis is a chronic immune-mediated colonic inflammatory bowel disease with unknown etiology(Du & Ha, 2020; Gros & Kaplan, 2023). There are different UC activity scoring systems for assessing endoscopic disease activity status, but there is no consensus on how to define fully sustained remission(Fenton et al., 2021; Travis et al., 2011). Many clinical studies have found that achieving mucosal healing usually suggests that patients are more likely to achieve sustained remission with reduced hospitalization rates, surgery rates, and lower rates of intestinal complications(Papi & Aratari, 2014; Pineton de Chambrun et al., 2010). However, there is no standardized definition of mucosal healing, and endoscopic healing does not mean complete disappearance of inflammation or injury(Nakase et al., 2021). Fenton et al. 's study also found that compared with active UC, genes in remission phase showed reduced levels of inflammatory characteristics, but they are not completely reduced, suggesting that mucosal healing in the remission phase of UC has not been fully achieved(Fenton et al., 2021). Therefore, elucidating the molecular mechanisms of remission in UC and inducing long-term remission or even cure in UC patients remains an urgent need. In this study, we extracted transcriptional profiles of normal and UC samples from GEO, and the results revealed that HMGCS2 was significantly downregulated in both inflammed and remission samples of UC patients as compared to controls.

Previous studies in liver cancer cell lines have found that HMGCS2 may significantly induce fatty acid β-oxidation by rapid consumption of acetyl-coenzyme A, and the knockdown of HMGCS2 may cause the accumulation of acetyl-coenzyme A, thereby negatively inhibiting fatty acid β-oxidation(Vila-Brau et al., 2011). Also, HMGCS2-mediated fatty acid β-oxidation may act as a protective mechanism to inhibit the activation of M1 macrophages and attenuate the inflammatory response of intestinal cells induced by TNF-α(Kim et al., 2019; Kim et al., 2021; Zhang et al., 2022). We performed in vitro study that Caco-2 and HT-29 cells lacking HMGCS2 were generated using lentiviral shRNA vectors, and RNA sequencing was performed to retrieve Hub^HMGCS2−FA.

KEGG analysis showed that the DEGs in the two groups of cells were mainly enriched in cytokine receptor interaction pathway and fatty acid metabolism pathway. Many inflammatory cytokines play a key role in the pathophysiological process of UC through their pro-inflammatory effects, including IL-1, IL-6, and TNF-α(Xin et al., 2020), which we have confirmed in previous cell experiments. The results of this study showed that the fatty acid metabolic pathway was significantly down-regulated in both cell lines, which warrants further investigation. By overlapping the leading-edge genes between Caco-2 and HT-29 cells, we identified 10 candidate genes associated with HMGCS2 (Hub^HMGCS2−FA). Further analysis of GSE38713 and GSE59071 datasets showed that fatty acid metabolism pathway was significantly down-regulated not only in inflammatory tissues, but also in remission tissues. Moreover, HMGCS2 was significantly positively correlated with fatty acid metabolism pathway and multiple pairs of genes from Hub^HMGCS2−FA panel. Therefore, although UC patients have met the existing clinical diagnostic criteria for remission phase, there are still persistent damage and alterations. It is worth improving the diagnostic criteria of remission phase and finding new biomarkers or therapeutic targets. We then established risk score model^HMGCS2−FA to predict UC patients using GEO datasets and found that it performed well in distinguishing UC patients in remission from normal controls (AUC:0.85-1). These studies indicate a protective role of HMGCS2- associated hub genes in the regulation of epithelial cell damage in active and remission UC patients, which may be a potential therapeutic target for patients with remission UC.

To the best of our knowledge, this study is the first to investigate the role of HMGCS2 in UC patients in remission phase, and established HMGCS2 knockdown cell lines for RNA sequencing analysis. Combined with the GEO database, these findings collectively indicate that during the remission phase of UC, the expression and function of genes related to fatty acid metabolism significantly differed from those in normal controls and did not reach real remission. The results of the risk score prediction model showed that HMGCS2-associated hub gene had high diagnostic ability. The HMGCS2-associated hub genes might be regarded as a novel and effective therapeutic target for inducing long-term remission or even radical cure in future treatments for UC patients. While, multi-center studies with large sample size of UC patients in not only active phase but also remission phase are needed, providing a new direction for future research.

In conclusion, this study found that persistent mucosal injury still existed in the remission phase of UC with the downregulation of HMGCS2 expression and HMGCS2-associated fatty acid metabolism pathway. Therefore, HMGCS2-associated hub genes may serve as potential biomarkers for identifying UC patients in not only active phase but also remission phase and may be promising therapeutic targets for UC.

Funding

This study was funded by National Natural Science Foundation of China (No. 81500425), Shandong Province Natural Science Foundation (No. ZR2021MH183) and Shandong Province Natural Science Foundation (No. ZR2021MH362).

Availability of data

The omics data, encompassing RNAseq dataset from this study, have been deposited in the BioProject database at the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/bioproject/) under the accession number PRJNA1094450.

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No competing interests reported.

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The HMGCS2-associated hub genes as promising targets for ulcerative colitis patients

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Abstract

Figures

Introduction

Materials and Methods

Cell culture and transfection

Western Blot Analysis

Total RNA extraction

RNA sequencing

RNA Sequencing Data Analysis

Screening Gene Chip datasets

Establishment of risk score-related prediction model

Statistical analyses

Result

HMGCS2 knockdown downregulated fatty acid metabolism pathway and its leading edges

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1