Multi-omics approaches for revealing the etiology of cancer: from genomics, exposomics, metabolomics to system epidemiology / 中华流行病学杂志

Identifying risk factors of the disease are one of the main tasks of epidemiology. With the advancement of omics technologies (e.g., genome, transcriptome, proteome, metabolome, and exposome), cancer etiology research has entered the stage of systems epidemiology. Genomic research identifies cancer susceptibility loci and uncovers their biological mechanisms. Exposomic research investigates the impact of environmental factors on biological processes and disease risks. The metabolome is downstream of biological regulatory networks, reflecting the effects of the gene, environment, and their interactions, which can help elucidate the biological mechanisms of genetic and environmental risk factors and identify new biomarkers. Here, we reviewed the applications of genomic, exposomic, and metabolomic studies in the etiologic research on cancer. We summarized the importance of multi-omics approaches and systems epidemiology in cancer etiology research and outlined future perspectives.

Advances in molecular function of p62 protein and its role in diseases / 生物工程学报

Sequestosome 1 (SQSTM1/p62) is a selective autophagy adaptor protein that plays an important role in the clearance of proteins to be degraded as well as in the maintenance of cellular proteostasis. p62 protein has multiple functional domains, which interact with several downstream proteins to precisely regulate multiple signaling pathways, thereby linking p62 to oxidative defense systems, inflammatory responses and nutrient sensing. Studies have shown that mutation or abnormal expression of p62 is closely related to the occurrence and development of various diseases, including neurodegenerative diseases, tumors, infectious diseases, genetic diseases and chronic diseases. This review summarizes the structural features and molecular functions of p62. Moreover, we systematically introduce its multiple functions in protein homeostasis and regulation of signaling pathways. Furthermore, the complexity and versatility of p62 in the occurrence and development of diseases are summarized, with the aim to provide a reference for understanding the function of p62 protein and facilitating related disease research.

Spatial transcriptome analysis of long non-coding RNAs reveals tissue specificity and functional roles in cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Long non-coding RNAs (lncRNAs) play a significant role in maintaining tissue morphology and functions, and their precise regulatory effectiveness is closely related to expression patterns. However, the spatial expression patterns of lncRNAs in humans are poorly characterized. Here, we constructed five comprehensive transcriptomic atlases of human lncRNAs covering thousands of major tissue samples in normal and disease states. The lncRNA transcriptomes exhibited high consistency within the same tissues across resources, and even higher complexity in specialized tissues. Tissue-elevated (TE) lncRNAs were identified in each resource and robust TE lncRNAs were refined by integrative analysis. We detected 1 to 4684 robust TE lncRNAs across tissues; the highest number was in testis tissue, followed by brain tissue. Functional analyses of TE lncRNAs indicated important roles in corresponding tissue-related pathways. Moreover, we found that the expression features of robust TE lncRNAs made them be effective biomarkers to distinguish tissues; TE lncRNAs also tended to be associated with cancer, and exhibited differential expression or were correlated with patient survival. In summary, spatial classification of lncRNAs is the starting point for elucidating the function of lncRNAs in both maintenance of tissue morphology and progress of tissue-constricted diseases.

Research progress on genome-guided precision oncology and development ideas of antitumor Chinese medicine / 中国中药杂志

Genome-guided oncology refers to a new treatment concept that transcends histological classification and pathological ty-ping and uses drugs according to the genetic characteristics of tumors. New drug development technology and clinical trial design based on this concept provide new ideas for the clinical application of precision oncology. The multi-component and multi-target characteristics of Chinese medicine provide rich resources for the development of tumor-targeting drugs from natural products, and the design of the master protocol trial aiming at the characteristics of precision oncology supports the rapid clinical screening of effective tumor-targeting drugs. The emergence of the synthetic lethality strategy breaks through the bottleneck that the drug can only target the oncogene but cannot do anything to the tumor suppressor gene with the loss-of-function mutation in the past. With the rapid development of high-throughput sequencing technology, the cost of sequencing is also decreasing. For the development of tumor-targeting drugs, how to keep up with the update speed of target information is a difficult problem of concern. Based on the integration of innovative ideas and me-thods of precision oncology, network pharmacology, and synthetic lethality strategy on synthetic lethal interaction network of antitumor Chinese medicine compatibility formula design, and the combination of improvement of innovative clinical trial methods, such as master protocol trial, basket trial, and umbrella trial, unique advantages of Chinese medicine are expected to be exerted beyond the antibody-based drugs and small molecule-based drugs and corresponding targeted drugs are potentially developed for clinical application.

Mechanism of Cistanches Herba in treatment of cancer-related fatigue based on network pharmacology and experimental verification / 中国中药杂志

This study aimed to explore the mechanism of Cistanches Herba in the treatment of cancer-induced fatigue(CRF) by network pharmacology combined with in vivo and in vitro experiments to provide a theoretical basis for the clinical medication. The chemical constituents and targets of Cistanches Herba were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The targets of CRF were screened out by GeneCards and NCBI. The common targets of traditional Chinese medicine and disease were selected to construct a protein-protein interaction(PPI) network, followed by Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. A visual signal pathway rela-ted to Chinese medicine and disease targets was constructed. The CRF model was induced by paclitaxel(PTX) in mice. Mice were divided into a control group, a PTX model group, and low-and high-dose Cistanches Herba extract groups(250 and 500 mg·kg~(-1)). The anti-CRF effect in mice was evaluated by open field test, tail suspension test, and exhaustive swimming time, and the pathological morphology of skeletal muscle was evaluated by hematoxylin-eosin(HE) staining. The cancer cachexia model in C2C12 muscle cells was induced by C26 co-culture, and the cells were divided into a control group, a conditioned medium model group, and low-, medium-, and high-dose Cistanches Herba extract groups(62.5, 125, and 250 μg·mL~(-1)). The reactive oxygen species(ROS) content in each group was detected by flow cytometry, and the intracellular mitochondrial status was evaluated by transmission electron microscopy. The protein expression levels of hypoxia-inducible factor-1α(HIF-1α), BNIP3L, and Beclin-1 were detected by Western blot. Six effective constituents were screened out from Cistanches Herba. The core genes of Cistanches Herba in treating CRF were AKT1, IL-6, VEGFA, CASP3, JUN, EGFR, MYC, EGF, MAPK1, PTGS2, MMP9, IL-1B, FOS, and IL10, and the pathways related to CRF were AGE-RAGE and HIF-1α. Through GO enrichment analysis, it was found that the main biological functions involved were lipid peroxidation, nutrient deficiency, chemical stress, oxidative stress, oxygen content, and other biological processes. The results of the in vivo experiment showed that Cistanches Herba extract could significantly improve skeletal muscle atrophy in mice to relieve CRF. The in vitro experiment showed that Cistanches Herba extract could significantly reduce the content of intracellular ROS, the percentage of mitochondrial fragmentation, and the protein expression of Beclin-1 and increase the number of autophagosomes and the protein expression of HIF-1α and BNIP3L. Cistanches Herba showed a good anti-CRF effect, and its mechanism may be related to the key target proteins in the HIF-1α signaling pathway.

Generating universal chimeric antigen receptor expressing cell products from induced pluripotent stem cells: beyond the autologous CAR-T cells / 中华医学杂志(英文版)

Adoptive therapeutic immune cells, such as chimeric antigen receptor (CAR)-T cells and natural killer cells, have established a new generation of precision medicine based on which dramatic breakthroughs have been achieved in intractable lymphoma treatments. Currently, well-explored approaches focus on autologous cells due to their low immunogenicity, but they are highly restricted by the high costs, time consumption of processing, and the insufficiency of primary cells in some patients. Induced pluripotent stem cells (iPSCs) are cell sources that can theoretically produce indefinite well-differentiated immune cells. Based on the above facts, it may be reasonable to combine the iPSC technology and the CAR design to produce a series of highly controllable and economical "live" drugs. Manufacturing hypoimmunogenic iPSCs by inactivation or over-expression at the genetic level and then arming the derived cells with CAR have emerged as a form of "off-the-shelf" strategy to eliminate tumor cells efficiently and safely in a broader range of patients. This review describes the reasonability, feasibility, superiority, and drawbacks of such approaches, summarizes the current practices and relevant research progress, and provides insights into the possible new paths for personalized cell-based therapies.

Mammalian DMRTs: Structure, function and relationship with cancer / 生理学报

DMRT, a gene family related to sexual determination, encodes a large group of transcription factors (DMRTs) with the double-sex and mab-3 (DM) domain (except for DMRT8), which is able to bind to and regulate DNAs. Current studies have shown that the DMRT gene family plays a critical role in the development of sexual organs (such as gender differentiation, gonadal development, germ cell development, etc.) as well as extrasexual organs (such as musculocartilage development, nervous system development, etc.). Additionally, it has been suggested that DMRTs may be involved in the cancer development and progression (such as prostate cancer, breast cancer, lung cancer, etc.). This review summarizes the research progress about the mammalian DMRTs' structure, function and its critical role in cancer development, progression and therapy (mainly in human and mice), which suggests that DMRT gene could be a candidate gene in the study of tumor formation and therapeutic strategy.

Emerging role of long non-coding RNA JPX in malignant processes and potential applications in cancers / 中华医学杂志(英文版)

Long non-coding RNAs (lncRNAs) reportedly function as important modulators of gene regulation and malignant processes in the development of human cancers. The lncRNA JPX is a novel molecular switch for X chromosome inactivation and differentially expressed JPX has exhibited certain clinical correlations in several cancers. Notably, JPX participates in cancer growth, metastasis, and chemoresistance, by acting as a competing endogenous RNA for microRNA, interacting with proteins, and regulating some specific signaling pathways. Moreover, JPX may serve as a potential biomarker and therapeutic target for the diagnosis, prognosis, and treatment of cancer. The present article summarizes our current understanding of the structure, expression, and function of JPX in malignant cancer processes and discusses its molecular mechanisms and potential applications in cancer biology and medicine.

Advances in research of Musashi2 in solid tumors / 南方医科大学学报

RNA binding protein (RBP) plays a key role in gene regulation and participate in RNA translation, modification, splicing, transport and other important biological processes. Studies have shown that abnormal expression of RBP is associated with a variety of diseases. The Musashi (Msi) family of mammals is an evolutionarily conserved and powerful RBP, whose members Msi1 and Msi2 play important roles in the regulation of stem cell activity and tumor development. The Msi family members regulate a variety of biological processes by binding and regulating mRNA translation, stability and downstream cell signaling pathways, and among them, Msi2 is closely related to embryonic growth and development, maintenance of tumor stem cells and development of hematological tumors. Accumulating evidence has shown that Msi2 also plays a crucial role in the development of solid tumors, mainly by affecting the proliferation, invasion, metastasis and drug resistance of tumors, involving Wnt/β-catenin, TGF-β/SMAD3, Akt/mTOR, JAK/STAT, Numb and their related signaling pathways (Notch, p53, and Hedgehog pathway). Preclinical studies of Msi2 gene as a therapeutic target for tumor have achieved preliminary results. This review summarizes the molecular structure, physiological function, role of Msi2 in the development and progression of various solid tumors and the signaling pathways involved.

Exploratory screening of potential pan-cancer biomarkers based on The Cancer Genome Atlas database / 北京大学学报(医学版)

OBJECTIVE@#To screen potential pan-cancer biomarkers based on The Cancer Genome Atlas (TCGA) database, and to provide help for the diagnosis and prognosis assessment of a variety of cancers.@*METHODS@#"GDC Data Transfer Tool" and "GDCRNATools" packages were used to obtain TCGA database. After data sorting, a total of 13 cancers were selected for further analysis. False disco-very rate (FDR) < 0.05 and fold change (FC) >1.5 were used as the differential expression criteria to screen genes and miRNAs that were up- or down-regulated in all the 13 cancers. In the receiver operating characteristic curve (ROC curve), the area under the curve (AUC), the best cut-off value and the corresponding sensitivity and specificity were used to reflect diagnostic significance. The Kaplan-Meier method was used to calculate the survival probability and then the log-rank test was performed. Hazard ratio (HR) was calculated to reflect prognostic evaluation significance. DAVID tool were used to perform GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for differentially expressed genes. STRING and TargetScan tools were used to analyze the regulatory network of differentially expressed genes and miRNAs.@*RESULTS@#A total of 48 genes and 2 miRNAs were differentially expressed in all the 13 cancers. Among them, 25 genes were up-regulated, 23 genes and 2 miRNAs were down-regulated. Most differentially expressed genes and miRNAs had good ability to distinguish between the cases and controls, with AUC, sensitivity and specificity up to 0.8-0.9. Survival analysis results show that differentially expressed genes and miRNAs were significantly associated with patient survival in a variety of cancers. Most up-regulated genes were risk factors for patient survival (HR>1), while most down-regulated genes were protective factors for patient survival (0 < HR < 1). The enrichment analysis of GO and KEGG showed that the differentially expressed genes were mostly enriched in biological events related to cell proliferation. In the regulatory network analysis, a total of 13 differentially expressed genes and 2 differentially expressed miRNAs had regulatory and interaction relationships.@*CONCLUSION@#The 48 genes and 2 miRNAs that were differentially expressed in 13 cancers may serve as potential pan-cancer biomarkers, providing help for the diagnosis and prognosis evaluation of a variety of cancers, and providing clues for the development of broad-spectrum tumor therapeutic targets.

MicroRNAs: understanding their role in gene expression and cancer / MicroRNAs: entendendo seu papel como reguladores da expressão gênica e seu envolvimento no câncer

ABSTRACT MicroRNAs are small RNA molecules that regulate gene expression in cells. These small molecules comprise 17 to 25 nucleotides and are able to recognize target messenger RNAs by sequence complementarity and regulate their protein translation. Different microRNAs are expressed in all human cells. There is over 2,500 microRNAs described in humans that are involved in virtually all biological processes. Given their role as gene expression regulators, these molecules have been widely investigated and are thought to be associated with some specific physiological and pathological conditions, being proposed as biomarkers. It has recently been reported that microRNAs are secreted outside cells and are involved in intercellular communication. MicroRNAs in biological fluids are named circulating and have been detected in all body fluids, although the expression profile is specific for each type. The major advantages of using circulating microRNAs as biological markers are the high stability of those molecules and the wide availability of samples. Also, given the individual nature of microRNA expression changes, these molecules have a high potential for use in personalized medicine. In fact, microRNA expression profile determination may support disease recognition and diagnosis, and can be used to monitor therapeutic responses and establish patient prognosis, assisting in choice of treatment. This review provides a general overview of microRNAs and discusses the importance of those molecules in cancer, for deeper understanding of their role in this disease.

RESUMO Os microRNAs são pequenas moléculas de RNAs que regulam a expressão gênica das células. Com entre 17 e 25 nucleotídeos, essas pequenas moléculas reconhecem RNA mensageiro-alvo, por meio da complementariedade entre as sequências, e regulam sua tradução proteica. Todas as células humanas expressam diversos microRNAs. De fato, existem mais de 2.500 microRNAs descritos em humanos, relacionados com praticamente todos os processos biológicos. Devido ao seu papel como reguladores da expressão gênica, essas moléculas têm sido estudadas e relacionadas com algumas condições fisiológicas e patológicas específicas, sendo propostas como biomarcadores. Recentemente, foi descoberto que os microRNAs são normalmente liberados para fora da célula, onde participam da comunicação intercelular. MicroRNAs presentes nos fluidos biológicos são chamados de circulantes e têm sido encontrados em todos os fluidos corporais, porém o perfil de expressão é específico para cada tipo. O uso de microRNAs circulantes como marcadores biológicos apresenta vantagens relacionadas com a alta estabilidade dessas moléculas e a facilidade de obtenção de amostra. Adicionalmente, considerando que as alterações em microRNAs são dependentes das condições individuais, essas moléculas apresentam alto potencial de uso na medicina personalizada. De fato, a determinação do perfil de expressão de microRNAs pode auxiliar na identificação e diagnóstico de doenças, no monitoramento de respostas terapêuticas e na definição do prognóstico dos pacientes, auxiliando na escolha do tratamento. Nesta revisão são apresentados aspectos gerais dos microRNAs, e discute-se a importância dessas moléculas no câncer, visando a uma melhor compreensão de seu papel nessa doença.

Targeting "undruggable" c-Myc protein by synthetic lethality / 医学前沿

Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting "undruggable" proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

Proteins moonlighting in tumor metabolism and epigenetics / 医学前沿

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal - moonlighting protein - metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

Discovery and activity verification of reniformin A as an anti-tumor leading compound / 中国中药杂志

Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.

The role of nuclear receptor transcription factor NR2F6 in tumor / 生物工程学报

Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is a member of orphan nuclear receptors, which is expressed in major tissues and organs of the human body, and plays an important role in the regulation of various biological functions and gene expressions. Recent studies have shown that the expression of NR2F6 was up-regulated in a variety of malignant tumors and showed significant correlations with cancer progression. These findings triggered the widespread interest in understanding the relationship between NR2F6 and cancer development and progression. In addition, the latest studies have underscored that NR2F6 was involved in enhancing antitumor immune responses that could serve as a potential target for immune regulation. This review summarizes the biological functions of NR2F6 and its role in tumors, with the aim to provide new insights into effective cancer therapies.

Integration-based co-expression network analysis to investigate tumor-associated modules across three cancer types / 生物工程学报

In case/control gene expression data, differential expression (DE) represents changes in gene expression levels across various biological conditions, whereas differential co-expression (DC) represents an alteration of correlation coefficients between gene pairs. Both DC and DE genes have been studied extensively in human diseases. However, effective approaches for integrating DC-DE analyses are lacking. Here, we report a novel analytical framework named DC&DEmodule for integrating DC and DE analyses and combining information from multiple case/control expression datasets to identify disease-related gene co-expression modules. This includes activated modules (gaining co-expression and up-regulated in disease) and dysfunctional modules (losing co-expression and down-regulated in disease). By applying this framework to microarray data associated with liver, gastric and colon cancer, we identified two, five and two activated modules and five, five and one dysfunctional module(s), respectively. Compared with the other methods, pathway enrichment analysis demonstrated the superior sensitivity of our method in detecting both known cancer-related pathways and those not previously reported. Moreover, we identified 17, 69, and 11 module hub genes that were activated in three cancers, which included 53 known and three novel cancer prognostic markers. Random forest classifiers trained by the hub genes showed an average of 93% accuracy in differentiating tumor and adjacent normal samples in the TCGA and GEO database. Comparison of the three cancers provided new insights into common and tissue-specific cancer mechanisms. A series of evaluations demonstrated the framework is capable of integrating the rapidly accumulated expression data and facilitating the discovery of dysregulated processes.

Research advances on epigenetics and cancer metabolism / 浙江大学学报·医学版

Epigenetics concerns gene regulatory mechanisms beyond DNA sequence，such as DNA methylation，histone modification，chromatin remodeling，and non-coding RNA. Epigenetic mechanisms play a key role in development，cell fate decision and tumorigenesis. Chromatin modifications and its high order structure across our genome are major forms of epigenetic information，and its establishment and maintenance are closely related to cell metabolism. Metabolic changes in cancer cells include aerobic glycolysis，increased glucose uptake，abnormally active glutamine metabolism，and the use of non-conventional energy supply. These changes meet the vigorous energy and matter needs for the development and spread of cancer，and help tumor cells adapt to hypoxia microenvironment for their survival，proliferation，invasion and migration. There is a complex relationship between epigenetic modifications and cell metabolism in tumor. On the one hand，metabolites in tumor cells may act as cofactors，modification donors or antagonists of epigenetic enzymes，thus modulating the epigenetic landscape. On the other hand，epigenetic modifications can directly regulate the expression of metabolic enzymes，transporters，signaling pathway and transcription factors to affect cell metabolism. This article reviews the crosstalk between epigenetics and cancer metabolism，to explore their potential future applications in the treatment of tumors.

Interaction between RAS gene and lipid metabolism in cancer / 浙江大学学报·医学版

The gene is frequently mutated and abnormally activated in many cancers，and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors，which can be one of the key targets for anti-tumor therapy. gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways，such as lipid synthesis pathways and degradation pathways. Similarly，lipid metabolism can also modify and activate RAS protein and its downstream signaling pathways. This article overviews the current research progress on the interaction between lipid metabolism and ，to provide insight in therapeutic strategies of lipid metabolism for -driven tumors.

Effect of Nrf2 in tumor progression and its inhibitors in cancer therapy / 中国中药杂志

Nrf2 is the key transcription factor mainly for regulating oxidative homeostasis and cytoprotective responses against oxidative stress. Nrf2/Keap1 pathway is one of the most important cellular defense mechanisms against endogenous or exogenous oxidative stress. With its activation, a wide range of stress-related genes is transactivated to restore the cellular homeostasis. Recent studies revealed that the aberrant activation of Nrf2 is related to the malignant progression, chemotherapeutic drug resistance and poor prognosis. Nrf2 plays a crucial role in cancer malignancy and chemotherapeutic resistance by controlling the intracellular redox homeostasis through the activation of cytoprotective antioxidant genes. Nrf2 inhibitor containing many natural products has been deemed as a novel therapeutic strategy for human malignancies. This article reviews the progress of studies of the Nrf2/Keap1 pathway, and its biological impact in solid malignancies and molecular mechanisms for causing Nrf2 hyperactivation in cancer cells. In conclusion, we summarized the deve-lopment of Nrf2 inhibitors in recent years, in the expectation of providing reference for further drug development and clinical studies.