Colorectal cancer (CRC) is one of the most devastating diseases that accounts for numerous deaths worldwide. Tumor cell-autonomous pathways, such as the oncogenic signaling activation, significantly contribute to CRC progression and metastasis. Recent accumulating evidence suggests that the CRC microenvironment also profoundly promotes or represses this process. As the roles of the tumor microenvironment (TME) in CRC progression and metastasis is gradually uncovered, the importance of these non-cell-autonomous signaling pathways is appreciated. However, we are still at the beginning of this TME function exploring process. In this review, we summarize the current understanding of the TME in CRC progression and metastasis by focusing on the gut microbiota and host cellular and non-cellular components. We also briefly discuss TME-remodeling therapies in CRC.

/pdf/tumor-microenvironment-shapes-colorectal-cancer-progression-2f5el889.pdf

Tumor Microenvironment Shapes Colorectal Cancer Progression, Metastasis, and Treatment Responses

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.

/pdf/new-progresses-on-cell-surface-protein-hspa5-bip-grp78-in-vp40tocr.pdf

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

Background: Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. We aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders. Methods: Tumor and adjacent pancreas tissue samples were obtained following surgical resection from NAC-treated PDAC patients. SWATH-MS proteomic analysis was performed to identify and quantify proteins in tissue samples. Statistical analysis was performed to identify biomarkers for NAC response. Pathway analysis was performed to characterize affected canonical pathways in good- and poor-NAC responders. Results: A total of 3,156 proteins were identified, with 19 being were significantly upregulated in poor-responders compared to good-responders (log2 ratio > 2, p < 0.05). Those with the greatest ability to predict poor-NAC response were GRP78, CADM1, PGES2, and RUXF. Notably, canonical pathways that were significantly upregulated in good-responders included acute phase signaling and macrophage activation, indicating a heightened immune response in these patients. Conclusion: A novel biomarker signature for poor-NAC response in PDAC was identified.

/pdf/identification-of-novel-biomarkers-in-pancreatic-tumor-haiazflb1l.pdf

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy.

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.

/pdf/a-novel-oxidative-stress-and-ferroptosis-related-gene-mlqi391c.pdf

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

Spermine synthase (SMS) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that SMS is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive SMS reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, SMS was identified as the direct target of both methyltransferase like 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly bind to the m6A modification sites of SMS and inhibit mRNA degradation. Knockdown of METTL3 or IGF2BP3 significantly reduced the SMS protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.

/pdf/mettl3-igf2bp3-axis-mediates-the-proliferation-and-migration-1rsvpdid.pdf

METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification

Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma

Epithelium-specific Ets protein 3 (Ese-3), a member of the Ets family of transcription factors, plays an important role in the development of cancers. However, little is known concerning its role in colon cancer (CC). In this study, we demonstrate that the expression of Ese-3 is upregulated in CC tissues and elevated Ese-3 expression is relationship with advanced T stage (P=0.037) and poor disease-free survival (DFS, P=0.044). Univariate and multivariate cox regression analyses show that Ese-3 expression may be an independent prognostic value for CC patients. Moreover, Ese-3 knockdown suppresses CC cell proliferation in vitro and in vivo, while Ese-3 overexpression has the opposite result. Further, we first demonstrate that EHD2 and INPP4B are the downstream genes of Ese-3. Subsequent investigation find that EHD2 is downregulated in CC tissues and knockdown of EHD2 significantly increase CC cell proliferation in vitro and vivo. Our findings reveal that Ese-3 promotes CC cell proliferation by downregulating EHD2 and transactivating INPP4B, and targeting the pathway may be a promising therapeutic target for CC patients.

Ese-3 contributes to colon cancer progression by downregulating EHD2 and transactivating INPP4B.


 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.

/pdf/hspa5-repressed-ferroptosis-to-promote-colorectal-cancer-599ddodsb8.pdf

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

Pancreatic cancer (PAAD) is one of the most malignant cancers and immune microenvironment has been proved to be involved in pathogenesis of PAAD. m6A modification, related to the expression of m6A regulators, participates in the development of multiple cancers. However, the correlation between m6A regulators and immune microenvironment was largely unknown in PAAD. And because of the small sample size of pancreatic cancer in the TCGA database, it is not enough to draw a convincing conclusion. In the present study, we downloaded seven pancreatic cancer datasets with survival data and removed batch effects among these datasets to be used as the PAAD cohort to analyze the immune landscape of PAAD and the expression pattern of m6A regulators and divided the integrated dataset into cluster 1 and cluster 2 by consensus clustering for m6A regulators. Lower m6A regulators were found to be related to higher immune cell infiltration and a better survival. Moreover, we identified six m6A regulators and constructed the prognostic signature of m6A regulators. Patients with low-risk score had a higher response to immune checkpoint inhibitor and a longer overall survival. To figure out the underlying mechanism, we analyzed the cancer immunity cycle, most altered genes, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) in risk subtypes. In summary, the present study proved m6A regulators modulated the PAAD immune microenvironment. And risk scores served as predictive indicator for immunotherapy and played a prognostic role for PAAD patients. Our study provided novel therapeutic targets to improve immunotherapy efficacy.

Comprehensive Analysis of m6A RNA Methylation Regulators and the Immune Microenvironment to Aid Immunotherapy in Pancreatic Cancer.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Junqiang Li

Author Tools

Chat about Author

Papers

Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma

Ese-3 contributes to colon cancer progression by downregulating EHD2 and transactivating INPP4B.

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

Comprehensive Analysis of m6A RNA Methylation Regulators and the Immune Microenvironment to Aid Immunotherapy in Pancreatic Cancer.