Correlation Of The Biological Behavior Between Tumorigenesis And Placental Villi Development

Part ?:Villi-specific gene expression reveals novel prognostic biomarkers in multiple human cancersBackground:Despite many striking connections,the biological similarities between embryonic development and tumorigenesis have not been well explored.Development of the placental villi is a crucial process involving many cellular activities,including immunity,proliferation,and cell adhesion.Tumor cells may take advantage of similar biological behavior in tumorigenesis.Aim:By comparing the changes of chorionic villus samples and leaf chorionic samples from postpartum placental tissues,we explored the corresponding characteristics of tumors.It will provide a new way for the study of tumors and new targets for caneer diagnosis and treatment.Methods:We collected 36 chorionic villus samples at 6 to 10 weeks of gestation and 8 mature placentas and examined with Agilent whole genome expression microarray.Combined with transcriptome data of TCGA(The Cancer Genome Atlas)to bioinformatics analysis.Then we identified early villi-specific expression genes,and through GO(The Gene Ontology)and KEGG(Kyoko Encyclopedia of Genes and Genomes)to analyze the major biological functions and pathways,and to determine the changes of these villi-specific genes in pan-cancer and their relationship with the prognosis of cancer patients.Results:We designed a strategy to identify 237 villi-specific expression genes that are highly expressed in the villus as opposed to the mature placenta and then measured the expression levels of these genes in tumors.We found large changes in the expression of villi-specific genes in multiple types of cancer.These villi-specific genes showed distinct expression patterns and were primarily involved in three biological processes:immune-related(5 genes),proliferation-related(6 genes),and focal adhesion-related(8 genes),these genes were extracted from the corresponding enriched GO terms.We observed that these genes were also dysregulated at the genome level across several tumor types.Moreover,the expression of these three gene groups was associated with poor prognosis in a subset of tumors.Conclusions:Based on villi-specifie gene expression,this correlation study indieated the existence of common gene expression patterns between embryonic development and tumorigenesis.Therefore,a systematic analysis of villi-specific gene aberrations in various tumors could serve as an indicator for identifying novel prognostic biomarkers.Part ?:Indentify prognostic biomarkers for colorectal cancer by human villi development modelBackground:Tumorigenesis and embryogenesis have many similar biological characteristics,such as proliferation,invasion,metabolism and immunity,so trophoblast have been defined as "physiological metastasis" or "pseudo-malignant".The development of villi is a physiological process,which conforms to regular rules.However,tumorigenesis is a pathological process that is not regulated by the organism.We hypothesize that if the interactions between genes and genes in tumors off-track from the interactions in villi,it is more likely to develop into malignant tumors and have worse prognosis.Aim:By identifying the difference of gene co-expression pattern between human early villi and CRC(colorectal cancer),we try to find new biomarker for evaluating the prognosis of CRC.Methods:We collected tissue samples including human chorionic villus samples at 6 to 10 weeks of gestation(n=15)and leaf chorionic samples from postpartum placental tissue(n=6),then extracted RN A and carried out RNA sequencing.We processed bioinformatics analysis in combination with multi-stage CRC transcriptome data,including normal(n=12),low-grade adenoma(n=21),high-grade adenoma(n=30),cancer(n=25)and TCGA(The Cancer Genome Atlas)CRC transcriptome data.Identification of disordered genes in colorectal cancer and then confirmed by immunohistochemical and cellular mechanism experiments.Results:We found that CRC progress and villi development involve many genes with similar biological behaviors,such as proliferation,immuriity,metabolism and invasion,but the genes of the relevant biological behavior are different.Then we filtered those genes,of which the interactions in CRC are far from that in villi.Twenty-four genes,such as CHPF,MMP14,COL5A2 etc were finally selected.Abnormal expression of the 24 genes was significantly associated with poor survival in six independent CRC cohorts(TCGA,GSE39084,GSE14333,GSE17536,GSE39582,GSE29621).CHPF has not been reported to be associated with CRC as far as we know,and we eondueted preliminary verifieation.Immunohistochemical results showed that CHPF was an independent prognostic factor for CRC,and studies on cell mechanism showed that CHPF could promote cell proliferation,inhibit cell apoptosis,and promote cell migration.Conclusions:Our study indicated that villi development is a reliable and strictly regulated model which can illuminate the trajectory of human cancer development and the interactions between genes and genes in CRC development are off-track from that in villi.The off-track interactions of gene may have some substantial impacts on CRC development and reveal novel prognostic biomarkers.Part ?:Multi-omics characteristic genes of villi and their correlation with pan-cancers prognosisBackground:Researchers pay more and more attention to the similarity between tumorigenesis and villi development,but at present,they mainly focus on the transcriptome level.With the development of technology,the emergence of various ornics techniques provides new opportunities for the study of biology and medical research.Generally,each feature of different omics is analyzed independently by univariate statistical method,this analysis ignores the relationship between different features and may miss key biological information.The multi-omics data integration analysis can provide more systematic and comprehensive information for biological systems.Therefore,multi-omics data analysis of villi can be a more robust model for cancer research.Aim:By identifying the multi-omics characteristic genes of villi,we seek for biomarkers that can predict the survival of cancer patients and provide new clues for cancer research.Methods:Chorionic villus tissues and leaf chorionic samples from postpartum placental tissue were collected and performed by DNA methylation microarray,RNA sequencing and protein spectrum experiment.Through bioinformatics analysis,the correlation between DNA methylation beta value and RNA sequencing TPM value,and RNA sequencing TPM value and protein expression value were assessed.Then,the DIABLO(Data Integration Analysis for Biomarker Discovery Using a Latent Component Method for Omics Studies)algorithm was used to identify multi-omics characteristic genes and then evaluate the prognosis of these characteristic genes.Results:After data analysis,the correlation between RNA and methylation was only 24.9%,while between RNA and protein was 17.8%.Using highly correlated protein/RNA to perform KEGG pathway enrichment analysis,results showed that many of them were enriched in metabolic pathways,indicating that more proteins were dynamically altered to adapt to the nutritional needs of biological behavior.Through DIABLO algorithm,57 multi-omics characteristic genes were identified.And then further filtering genes,whose RNA and protein expression were chnaged in the same trend,at the same time,the methylation level had changed significantly.Finally,19 characteristic genes were identified.Three genes were increaseed(CLDN6,GPT2,CHPF),and 16 genes were down-regulated(VWF,C7?CLEC3B,CNRIP1,SNTB1?RBP1,TRADD,RFTN1,SVEP1,RGCC?PRKAR2B,FABP5,CPQ,RRAS,CRIP2,IQGAP2),and these 19 genes were associated with the prognosis of TCGA pan-cancers.Conclusions:The low correlation among epigenome,transcriptome and proteome,indicated that the regulation of biological processes is very complex.Transcription and translation are two different biological processes.There are many reasons to explain the difference of gene expression,transcription regulation and protein expression,such as regulation of non-coding RNA,protein degradation,protein secretion,etc.Therefore,the correlation between gene and protein expression is low.In addition,multi-omics characteristic genes identified by villus multi-omics data can well predict the prognosis of patients,which indicates that multi-omics data is of great value in exploring the prognosis of tumors,and can provide a new method for the study of tumors.