Bioinformatic mining and validation of the effects of ferroptosis regulators on the prognosis and progression of pancreatic adenocarcinoma

Xu, Fangshi; Zhang, Zhengliang; Zhao, Yidi; Zhou, Yang; Pei, Honghong; Bai, Linquan

doi:10.1016/j.gene.2021.145804

Cited by 26 publications

(21 citation statements)

References 61 publications

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“…Previously, several valuable PDAC prognostic signatures have been constructed by using bioinformatics analysis. For example, signatures based on glycolysis, m6A, ferroptosis, immune, and extracellular vesicle predict 1-year OS for PDAC with AUC at 0.805, 0.736, 0.81, 0.755, and 0.640, respectively, which were similar to our study ( Xu et al, 2020 ; Chen et al, 2021 ; Song et al, 2021 ; Xu et al, 2021 ; Yuan et al, 2021 ). However, the number of patients included in the abovementioned studies ranged from 183 to 441 and were relatively low.…”

Section: Discussionsupporting

confidence: 88%

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma

Xiao

Jin-yin

et al. 2021

Front. Pharmacol.

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with an extremely low 5-year survival rate. Accumulating evidence has unveiled that inflammatory response promotes tumor progression, enhances angiogenesis, and causes local immunosuppression. Herein, we aim to develop an inflammatory related prognostic signature, and found it could be used to predict gemcitabine response in PDAC.Methods: PDAC cohorts with mRNA expression profiles and clinical information were systematically collected from the four public databases. An inflammatory response related genes (IRRGs) prognostic signature was constructed by LASSO regression analysis. Kaplan–Meier survival analysis, receiver operating characteristic analysis, principal component analysis, and univariate and multivariate Cox analyses were carried out to evaluate effectiveness, and reliability of the signature. The correlation between gemcitabine response and risk score was evaluated in the TCGA-PAAD cohort. The GDSC database, pRRophetic algorithm, and connectivity map analysis were used to predict gemcitabine sensitivity and identify potential drugs for the treatment of PDAC. Finally, we analyzed differences in frequencies of gene mutations, infiltration of immune cells, as well as biological functions between different subgroups divided by the prognostic signature.Results: We established a seven IRRGs (ADM, DCBLD2, EREG, ITGA5, MIF, TREM1, and BTG2) signature which divided the PDAC patients into low- and high-risk groups. Prognostic value of the signature was validated in 11 PDAC cohorts consisting of 1337 PDAC patients from 6 countries. A nomogram that integrated the IRRGs signature and clinicopathologic factors of PDAC patients was constructed. The risk score showed positive correlation with gemcitabine resistance. Two drugs (BMS-536924 and dasatinib) might have potential therapeutic implications in high-risk PDAC patients. We found that the high-risk group had higher frequencies of KRAS, TP53, and CDKN2A mutations, increased infiltration of macrophages M0, neutrophils, and macrophages M2 cells, as well as upregulated hypoxia and glycolysis pathways, while the low-risk group had increased infiltration of CD8+ T, naïve B, and plasma and macrophages M1 cells.Conclusion: We constructed and validated an IRRGs signature that could be used to predict the prognosis and gemcitabine response of patients with PDAC, as well as two drugs (BMS-536924 and dasatinib) may contribute to PDAC treatment.

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Section: Discussionsupporting

confidence: 88%

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma

Xiao

Jin-yin

et al. 2021

Front. Pharmacol.

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“…Moreover, prostate cancer patients with high SQLE expression are 8.3 times more likely to have lethal outcomes than that with low SQLE expression [61]. In pancreatic cancer, SQLE plays as a pivotal components of FR prognostic model and is proven to have cancer-promoting functions [62,63]. In the present study, we confirmed the overexpression of SQLE in mRNA and histological levels, and demonstrated that SQLE was capable of promoting the proliferative, migrative and invasive abilities of BC cells.…”

Section: Discussionsupporting

confidence: 78%

Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer

Tang

Zhao

et al. 2021

BMC Cancer

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Background Ferroptosis, a new form of programmed cell death, has great potential for cancer treatment. However, the roles of ferroptosis-related (FR) genes in breast cancer (BC) remain elusive. Materials and methods Using TCGA database, a novel FR risk signature was constructed through the Lasso regression analysis. Meanwhile, its prognostic value was assessed by a series of survival analyses. Besides, a nomogram was constructed to predict the overall survival rate (OSR) of individual at 1,3,5 year. Four validation cohorts (n = 2248), including METABRIC, GSE58812, GSE20685 and ICGC-KR datasets, were employed to test the prognostic value of FR risk signature. The effects of FR risk signature on BC immune microenvironment were explored by CIBERSORT algorithm and ssGSEA method. The histological expressions of FR risk genes were presented by HPA database. The biofunctions of SQLE were determined by qPCR, MTT, wound-healing and Transwell assays. Results We constructed a novel FR risk signature consisting of eight genes. High FR risk led a poor prognosis and was identified as an independent prognostic factor. Besides, A higher proportion of patients with luminal A type was observed in low-risk group (53%), while a higher proportion of patients with basal type in high-risk group (24%). FR risk score could discriminate the prognostic difference of most clinical subgroups, except for M1 stage, HER2 and basal types. Moreover, its prognostic value was successfully validated in other four cohorts. Through immune analyses, we found that the reduced infiltration levels of CD8+ and NK cells, whereas the enhanced activity of antigen presentation process appeared in high FR risk. Then, FR risk score was found to weakly correlate with the expressions of six immune checkpoints. Through the experiments in vitro, we confirmed that overexpression of SQLE could promote, whereas blocking SQLE could inhibit the proliferative, migrative and invasive abilities of BC cells. Conclusions FR risk signature was conducive to BC prognostic assessment. High FR risk level was closely associated with BC immunosuppression, but may not predict ICIs efficacy. Moreover, SQLE was identified as a crucial cancer-promoting gene in BC. Our findings provide new insights into prognostic assessment and molecular mechanism of BC.

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“…According to previous literature, during the EMT process, the high transcription level of SNAI1, TWIST1 and ZEB1 will increase the sensitivity of cells to ferroptosis ( Chen et al, 2021 ). Taken together, we believe that EMT of epithelial cells will increase the sensitivity of ferroptosis, and the occurrence of ferroptosis can enhance the transformation of epithelial cells to mesenchymal cells, which form a positive feedback mechanism loop ( Xu et al, 2021a ; Sun et al, 2021 ). To validate the clinical relevance of molecules in the gene regulatory network, we performed a validation of the ferroptosis marker in the TCGA-LUAD database.…”

Section: Resultsmentioning

confidence: 81%

“…On the contrary, ferroptosis tendency can enhance the development of EMT. When PTSG2, as a driver of ferroptosis, was blocked, the expression of N-cadherin was suppressed and the expression of E-cadherin was promoted, which suggested that inhibition of ferroptosis can lead to inhibition of EMT in parallel ( Xu et al, 2021a ). Not coincidentally, the ferroptosis promoter Erastin reduced the expression of E-cadherin, again suggesting that ferroptosis tendency may be engaged in the development of EMT ( Sun et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Erastin, which is an inducer of ferroptosis, can act on lung epithelial cells and causes de-epithelialize ( Sun et al, 2021 ). PTGS2 is another ferroptosis promotor, the silencing of which can inhibit the proliferation and migration of pancreatic cancer cells ( Xu et al, 2021a ). Combined with the conclusions in the previous literatures, EMT and ferroptosis tendency may form a positive feedback loop within a certain range.…”

Section: Introductionmentioning

confidence: 99%

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Single-Cell RNA-Seq Reveals the Promoting Role of Ferroptosis Tendency During Lung Adenocarcinoma EMT Progression

Yao

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Epithelial-mesenchymal transition (EMT) and ferroptosis are two important processes in biology. In tumor cells, they are intimately linked. We used single-cell RNA sequencing to investigate the regulatory connection between EMT and ferroptosis tendency in LUAD epithelial cells. We used Seurat to construct the expression matrix using the GEO dataset GSE131907 and extract epithelial cells. We found a positive correlation between the trends of EMT and ferroptosis tendency. Then we used SCENIC to analyze differentially activated transcription factors and constructed a molecular regulatory directed network by causal inference. Some ferroptosis markers (GPX4, SCP2, CAV1) were found to have strong regulatory effects on EMT. Cell communication networks were constructed by iTALK and implied that Ferro_High_EMT_High cells have a higher expression of SDC1, SDC4, and activation of LGALS9-HARVCR2 pathways. By deconvolution of bulk sequencing, the results of CIBERSORTx showed that the co-occurrence of ferroptosis tendency and EMT may lead to tumor metastasis and non-response to immunotherapy. Our findings showed there is a strong correlation between ferroptosis tendency and EMT. Ferroptosis may have a promotive effect on EMT. High propensities of ferroptosis and EMT may lead to poor prognosis and non-response to immunotherapy.

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Bioinformatic mining and validation of the effects of ferroptosis regulators on the prognosis and progression of pancreatic adenocarcinoma

Cited by 26 publications

References 61 publications

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma

Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer

Single-Cell RNA-Seq Reveals the Promoting Role of Ferroptosis Tendency During Lung Adenocarcinoma EMT Progression

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