Yang Song

Bio: Yang Song is an academic researcher. The author has co-authored 1 publications.

HSPA5 Repressed Ferroptosis to Promote Colorectal Cancer Development by Maintaining GPX4 Stability

Abstract: Background:Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown.Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. Methods:In this study, erastin was used to induce ferroptosis in CRC cells. Cell viability and apoptosis were assessed by CCK-8 and colony formation assayand annexin V/propidium iodide staining, respectively. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. Unfolded protein response-related proteins and GPX4 protein were analyzed by western blotting. The CRC datasetswere analyzed using the R software, GEPIA2 and TIMER2.0. Results:The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increasedduring ferroptosis. HSPA5 was found to attenuateerastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bounddirectly to GPX4 andthe interaction between HSPA5 and GPX4increased when treated with erastinfor a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to immune microenvironment in CRC patients.Conclusion:Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.

Prognostic prediction and immune infiltration analysis based on ferroptosis and EMT state in hepatocellular carcinoma

Abstract: Background Ferroptosis is one of the main mechanisms of sorafenib against hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) plays an important role in the heterogeneity, tumor metastasis, immunosuppressive microenvironment, and drug resistance of HCC. However, there are few studies looking into the relationship between ferroptosis and EMT and how they may affect the prognosis of HCC collectively. Methods We downloaded gene expression and clinical data of HCC patients from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for prognostic model construction and validation respectively. The Least absolute shrinkage and selection operator (LASSO) Cox regression was used for model construction. The predictive ability of the model was assessed by Kaplan–Meier survival analysis and receiver operating characteristic (ROC) curve. We performed the expression profiles analysis to evaluate the ferroptosis and EMT state. CIBERSORT and single-sample Gene Set Enrichment Analysis (ssGSEA) methods were used for immune infiltration analysis. Results A total of thirteen crucial genes were identified for ferroptosis-related and EMT-related prognostic model (FEPM) stratifying patients into two risk groups. The high-FEPM group had shorter overall survivals than the low-FEPM group (p<0.0001 in the TCGA cohort and p<0.05 in the ICGC cohort). The FEPM score was proved to be an independent prognostic risk factor (HR>1, p<0.01). Furthermore, the expression profiles analysis suggested that the high-FEPM group appeared to have a more suppressive ferroptosis status and a more active EMT status than the low- FEPM group. Immune infiltration analysis showed that the myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were highly enriched in the high-FEPM group. Finally, a nomogram enrolling FEPM score and TNM stage was constructed showing outstanding predictive capacity for the prognosis of patients in the two cohorts. Conclusion In conclusion, we developed a ferroptosis-related and EMT-related prognostic model, which could help predict overall survival for HCC patients. It might provide a new idea for predicting the response to targeted therapies and immunotherapies in HCC patients.

A novel oxidative stress- and ferroptosis-related gene prognostic signature for distinguishing cold and hot tumors in colorectal cancer

Abstract: Oxidative stress and ferroptosis exhibit crosstalk in many types of human diseases, including malignant tumors. We aimed to develop an oxidative stress- and ferroptosis-related gene (OFRG) prognostic signature to predict the prognosis and therapeutic response in patients with colorectal cancer (CRC). Thirty-four insertion genes between oxidative stress-related genes and ferroptosis-related genes were identified as OFRGs. We then performed bioinformatics analysis of the expression profiles of 34 OFRGs and clinical information of patients obtained from multiple datasets. Patients with CRC were divided into three OFRG clusters, and differentially expressed genes (DEGs) between clusters were identified. OFRG clusters correlated with patient survival and immune cell infiltration. Prognosis-related DEGs in three clusters were used to calculate the risk score, and a prognostic signature was constructed according to the risk score. In this study, patients in the low-risk group had better prognosis, higher immune cell infiltration levels, and better responses to fluorouracil-based chemotherapy and immune checkpoint blockade therapy than high-risk patients; these results were successfully validated with multiple independent datasets. Thus, low-risk CRC could be defined as hot tumors and high-risk CRC could be defined as cold tumors. To further identify potential biomarkers for CRC, the expression levels of five signature genes in CRC and adjacent normal tissues were further verified via an in vitro experiment. In conclusion, we identified 34 OFRGs and constructed an OFRG-related prognostic signature, which showed excellent performance in predicting survival and therapeutic responses for patients with CRC. This could help to distinguish cold and hot tumors in CRC, and the results might be helpful for precise treatment protocols in clinical practice.

Ferroptosis open a new door for colorectal cancer treatment

Abstract: Colorectal cancer (CRC) is the third highest incidence and the second highest mortality malignant tumor in the world. The etiology and pathogenesis of CRC are complex. Due to the long course of the disease and no obvious early symptoms, most patients are diagnosed as middle and late stages. CRC is prone to metastasis, most commonly liver metastasis, which is one of the leading causes of death in CRC patients. Ferroptosis is a newly discovered cell death form with iron dependence, which is driven by excessive lipid peroxides on the cell membrane. It is different from other form of programmed cell death in morphology and mechanism, such as apoptosis, pyroptosis and necroptosis. Numerous studies have shown that ferroptosis may play an important role in the development of CRC. For advanced or metastatic CRC, ferroptosis promises to open a new door in the setting of poor response to chemotherapy and targeted therapy. This mini review focuses on the pathogenesis of CRC, the mechanism of ferroptosis and the research status of ferroptosis in CRC treatment. The potential association between ferroptosis and CRC and some challenges are discussed.

Insights on Ferroptosis and Colorectal Cancer: Progress and Updates

Abstract: Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) benefit less from traditional therapies; hence, new therapeutic strategies may help improve the treatment response and prognosis of these patients. Ferroptosis is an iron-dependent type of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS), distinct from other types of regulated cell death. CRC cells, especially those with drug-resistant properties, are characterized by high iron levels and ROS. This indicates that the induction of ferroptosis in these cells may become a new therapeutic approach for CRC, particularly for eradicating CRC resistant to traditional therapies. Recent studies have demonstrated the mechanisms and pathways that trigger or inhibit ferroptosis in CRC, and many regulatory molecules and pathways have been identified. Here, we review the current research progress on the mechanism of ferroptosis, new molecules that mediate ferroptosis, including coding and non-coding RNA; novel inducers and inhibitors of ferroptosis, which are mainly small-molecule compounds; and newly designed nanoparticles that increase the sensitivity of cells to ferroptosis. Finally, the gene signatures and clusters that have predictive value on CRC are summarized.

New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19

Abstract: Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When the endoplasmic reticulum (ER) was stressed, HSPA5 translocated to the cell surface, the mitochondria, and the nucleus complexed with other proteins to execute its functions. On the cell surface, HSPA5/BiP/GRP78 can play diverse functional roles in cell viability, proliferation, apoptosis, attachments, and innate and adaptive immunity regulations, which lead to various diseases, including cancers and coronavirus disease 2019 (COVID-19). COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused the pandemic since the first outbreak in late December 2019. HSPA5, highly expressed in the malignant tumors, likely plays a critical role in SARS-CoV-2 invasion/attack in cancer patients via tumor tissues. In the current study, we review the newest research progresses on cell surface protein HSPA5 expressions, functions, and mechanisms for cancers and SARS-CoV-2 invasion. The therapeutic and prognostic significances and prospects in cancers and COVID-19 disease by targeting HSPA5 are also discussed. Targeting HSPA5 expression by natural products may imply the significance in clinical for both anti-COVID-19 and anti-cancers in the future.