Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

/pdf/erk-mapk-signalling-pathway-and-tumorigenesis-23yie24hev.pdf

ERK/MAPK signalling pathway and tumorigenesis.

Advances in Hypoxia-Inducible Factor Biology

Non-coding RNAs do not encode proteins and regulate various oncological processes. They are also important potential cancer diagnostic and prognostic biomarkers. Bioinformatics and translation omics have begun to elucidate the roles and modes of action of the functional peptides encoded by ncRNA. Here, recent advances in long non-coding RNA (lncRNA) and circular RNA (circRNA)-encoded small peptides are compiled and synthesized. We introduce both the computational and analytical methods used to forecast prospective ncRNAs encoding oncologically functional oligopeptides. We also present numerous specific lncRNA and circRNA-encoded proteins and their cancer-promoting or cancer-inhibiting molecular mechanisms. This information may expedite the discovery, development, and optimization of novel and efficacious cancer diagnostic, therapeutic, and prognostic protein-based tools derived from non-coding RNAs. The role of ncRNA-encoding functional peptides has promising application perspectives and potential challenges in cancer research. The aim of this review is to provide a theoretical basis and relevant references, which may promote the discovery of more functional peptides encoded by ncRNAs, and further develop novel anticancer therapeutic targets, as well as diagnostic and prognostic cancer markers.

/pdf/emerging-role-of-tumor-related-functional-peptides-encoded-13zj413eb1.pdf

Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA

Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for cancer prevention and treatment in the future.

/pdf/exosome-mediated-metabolic-reprogramming-the-emerging-role-5ervhrh9n4.pdf

Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression

Mammalian cells synthesize and release heterogeneous extracellular vesicles (EVs) which can be generally recognized as subclasses including exosomes, microvesicles (MVs), and apoptotic bodies (ABs), each differing in their biogenesis, composition and biological functions from others. EVs can originate from normal or cancer cells, transfer bioactive cargoes to both adjacent and distant sites, and orchestrate multiple key pathophysiological events such as carcinogenesis and malignant progression. Emerging as key messengers that mediate intercellular communications, EVs are being paid substantial attention in various disciplines including but not limited to cancer biology and immunology. Increasing lines of research advances have revealed the critical role of EVs in the establishment and maintenance of the tumor microenvironment (TME), including sustaining cell proliferation, evading growth suppression, resisting cell death, acquiring genomic instability and reprogramming stromal cell lineages, together contributing to the generation of a functionally remodeled TME. In this article, we present updates on major topics that document how EVs are implicated in proliferative expansion of cancer cells, promotion of drug resistance, reprogramming of metabolic activity, enhancement of metastatic potential, induction of angiogenesis, and escape from immune surveillance. Appropriate and insightful understanding of EVs and their contribution to cancer progression can lead to new avenues in the prevention, diagnosis and treatment of human malignancies in future medicine.

/pdf/extracellular-vesicles-in-the-tumor-microenvironment-old-4ol8ypzdss.pdf

Extracellular vesicles in the tumor microenvironment: old stories, but new tales.

It has been a long debate whether the 98% 'non-coding' fraction of human genome can encode functional proteins besides short peptides. With full-length translating mRNA sequencing and ribosome profiling, we found that up to 3330 long non-coding RNAs (lncRNAs) were bound to ribosomes with active translation elongation. With shotgun proteomics, 308 lncRNA-encoded new proteins were detected. A total of 207 unique peptides of these new proteins were verified by multiple reaction monitoring (MRM) and/or parallel reaction monitoring (PRM); and 10 new proteins were verified by immunoblotting. We found that these new proteins deviated from the canonical proteins with various physical and chemical properties, and emerged mostly in primates during evolution. We further deduced the protein functions by the assays of translation efficiency, RNA folding and intracellular localizations. As the new protein UBAP1-AST6 is localized in the nucleoli and is preferentially expressed by lung cancer cell lines, we biologically verified that it has a function associated with cell proliferation. In sum, we experimentally evidenced a hidden human functional proteome encoded by purported lncRNAs, suggesting a resource for annotating new human proteins.

A hidden human proteome encoded by 'non-coding' genes.

Background: The prognosis of esophageal squamous cell carcinoma (ESCC) is generally poor, and the identification of molecular markers related to the regulation of ESCC invasion and migration is important. Methods and Results: In this study, we report that ring finger protein-128 (RNF128) enhances the invasiveness and motility of ESCC cells by using transwell assays and Western blotting. A xenograft nude mouse model showed that RNF128 promotes the metastasis of ESCC cells in the lung. A signal pathway analysis identified the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK)/matrix matalloproteinases 2 (MMP-2) cascade as a mediator of RNF128-induced enhancement of ESCC progression. Inhibition experiments using inhibitors of EGFR, ERK kinase (MEK)/extracellular-signal-regulated-kinase (ERK), and MMP-2 reversed this progression. Co-immunoprecipitation demonstrated that RNF128 promotes the activation of the EGFR/ERK/MMP-2 pathway by interacting with p53 and p53 interacting with EGFR. Conclusion: Our results establish the functional role of RNF128 in driving the invasion and metastasis of ESCC through the EGFR/MAPK/MMP-2 pathway, implicating its potential as a candidate therapeutic target and prognostic biomarker for ESCC.

https://www.mdpi.com/2072-6694/11/6/840/pdf

RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma.

Exosomes are deliverers of critically functional proteins, capable of transforming target cells in numerous cancers, including hepatocellular carcinoma (HCC). We hypothesize that the motility of HCC cells can be featured by comparative proteome of exosomes. Hence, we performed the super-SILAC-based MS analysis on the exosomes secreted by three human HCC cell lines, including the non-motile Hep3B cell, and the motile 97H and LM3 cells. More than 1400 exosomal proteins were confidently quantified in each MS analysis with highly biological reproducibility. We justified that 469 and 443 exosomal proteins represented differentially expressed proteins (DEPs) in the 97H/Hep3B and LM3/Hep3B comparisons, respectively. These DEPs focused on sugar metabolism-centric canonical pathways per ingenuity pathway analysis, which was consistent with the gene ontology analysis on biological process enrichment. These pathways included glycolysis I, gluconeogenesis I and pentose phosphate pathways; and the DEPs enriched in these pathways could form a tightly connected network. By analyzing the relative abundance of proteins and translating mRNAs, we found significantly positive correlation between exosomes and cells. The involved exosomal proteins were again focusing on sugar metabolism. In conclusion, motile HCC cells tend to preferentially export more sugar metabolism-associated proteins via exosomes that differentiate them from non-motile HCC cells.

Motile hepatocellular carcinoma cells preferentially secret sugar metabolism regulatory proteins via exosomes.

Human microproteins encoded by long non‐coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493‐encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA‐binding protein PABPC4 and transferred to ribosomes for translation of a 95‐amino‐acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N‐terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK‐mediated AKT phosphorylation. Moreover, the formation of the SMIM26‐AGK‐SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493‐encoded microprotein SMIM26 and establishes its anti‐metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers.

LINC00493‐encoded microprotein SMIM26 exerts anti‐metastatic activity in renal cell carcinoma

A five-protein prognostic signature with GBP2 functioning in immune cell infiltration of clear cell renal cell carcinoma

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