Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer.

Abstract: H19 is an imprinted oncofetal non-coding RNA recently shown tobe the precursor of miR-675. The pathophysiological roles of H19and its mature product miR-675 to carcinogenesis have, however,notbeendefined.Byquantitativereversetranscription–polymerasechain reaction, both H19 and miR-675 were found to be upregu-lated in human colon cancer cell lines and primary humancolorectal cancer (CRC) tissues compared with adjacent non-cancerous tissues. Subsequently, the tumor suppressorretinoblas-toma (RB) was confirmed to be a direct target of miR-675 as themicroRNA suppressed the activity of the luciferase reporter car-rying the 3#-untranslated region of RB messenger RNA that con-tains the miR-675-binding site. Suppression of miR-675 bytransfection with anti-miR-675 increased RB expression and atthe same time, decreased cell growth and soft agar colony forma-tionin human coloncancercells. Reciprocally, enhanced miR-675expression by transfection with miR-675 precursor decreased RBexpression, increased tumor cell growth and soft agar colony for-mation. Moreover, the inverse relationship between the expres-sions of RB and H19/miR-675 was also revealed in human CRCtissues and colon cancer cell lines. Our findings demonstrate thatH19-derived miR-675, through downregulation of its target RB,regulates the CRC development and thus may serve as a potentialtarget for CRC therapy.IntroductionColorectal cancer (CRC) is the third most common cancer worldwidewith an estimated 1 million new cases and a half million deaths eachyear (1). Screening for CRC from curable early stages has the poten-tial to reduce both the incidence and mortality of the disease (2).Although 5 year mortality rates of CRC have slightly declined overthe last three decades, there is still a pressing need to identify newprognostic biomarkers and therapeutic targets for this disease. Fur-thermore, the underlying pathophysiological mechanisms of CRC de-velopment remain elusive (1–4).MicroRNAs (miRNAs) are 19- to 25-nucleotide regulatory non-codingRNAsthatareinitiallyexpressedashairpintranscriptsofprimarymiRNA.TheseprimarymiRNAhairpinsarecleavedbytwoRNAaseIIIenzymes, Drosha and Dicer, to generate mature miRNAs. MiRNAsregulate the expressions of a wide variety of genes by translation re-pression or promoting RNA degradation and are important in the regu-lation of various cellular processes, such as cellular proliferation,differentiation and apoptosis (5–7). To date, .723 human miRNAsare annotatedinthe miRBase registry(miRBaseversion 11.0), but mostof the genes regulated by human miRNAs are not well defined.Dysregulation of a specific spectrum of miRNAs in human malig-nancies is frequently observed. Emerging evidence suggests miRNAsfunction as both tumor suppressors and oncogenes. About 50% ofannotated human miRNAs located at chromosomal regions involvedin loss of heterozygosity, amplification or breakpoints that are asso-ciated with cancers (5,7,8). The miRNAs downregulated in humancancers indicate that they may function as tumor suppressors. Let-7,which targets the oncogene RAS, has shown to be downregulated inBCL2, are downregulated in chronic lymphocytic leukemias (10).Expression levels of miR-143 that targets ERK5 and miR-145 werefound to be decreased in colon cancer (11). In contrast, the miRNAsupregulated in cancers may function as oncogenes. MiR-155 and itshost gene BIC are highly expressed in several types of B-cell lym-phoma (12). The miR-17-92 cluster, which is located on chromosome13q31, is activated by the oncogene c-Myc and is highly expressed inB-cell lymphoma and lung cancer (13). Therefore, the importance ofmiRNAs acting as a new layer of gene regulation in tumorigenesis isemerging.H19 is a paternally imprinted (maternally expressed) oncofetalgene and is located on chromosome 11p15.5, close to the IGF II genelocus. The H19 gene does not encode for a protein but instead codesfor a capped, spliced and polyadenylated 2.7 kb RNA (14–16). H19 ishighly expressed from the early stages of embryogenesis to fetal lifein many organs including the fetal adrenal, liver and placenta but isnearly completely downregulated postnatally (17).Emerging evidence showed that H19 expression was upregulated inmany cancers including CRC (18,19), hepatocellular carcinoma(20), testicular cancer (21), choriocarcinoma (22), esophageal cancer(18), ovarian cancer(23), breast cancer (24) and bladder cancer (25,26),with or without the loss of imprinting. Patients with more H19-positive bladder cancer cells are potentially at higher risk of recurrentdisease (27). In the tumor formed by the injection of choriocarcinomaJar and JEG-3 cells into the nude mice, the H19 RNA level is higherthan those cells before the injection (28). Similarly, the H19 RNAlevel is greatly enhanced in tumor of human bladder carcinoma cellsformed in nude mice (25). The overexpression of H19 in cancertissues hints for its oncogenic function, but the exact underlyingmechanism is still not clear. Recently, H19 was reported to be theprimary miRNA precursor of miR-675 in both human and mice (29).As both H19 and miRNAs are believed to be involved in tumorio-genesis, this prompted us to speculate that the tumoriogenesis processinduced by H19 may be mediated through miR-675. Therefore, in thisstudy, we investigated the pathophysiological roles of H19 and miR-675 in CRC carcinogenesis. Furthermore, using in silico predictionand in vitro functional assays, we confirmed retinoblastoma (RB)protein as a putative direct target of miR-675. This verification ofthe oncogenic function of H19-miR-675-RB in CRC suggests thatthis pathway may serve as the potential target for cancer therapy.Materials and methods

Cancer stem cells in the development of liver cancer

Abstract: Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.

Cell adhesion system and human cancer morphogenesis

Abstract: Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced in human cancers. Reduced intercellular adhesiveness allows cancer cells to disobey the social order, resulting in destruction of histological structure, which is the morphological hallmark of malignant tumors. Reduced intercellular adhesiveness is also indispensable for cancer invasion and metastasis. A tumor-suppressor gene product, E-cadherin, and its undercoat proteins, catenins, which connect cadherins to actin filaments, are located at lateral borders, concentrating on adherens junctions, of epithelial cells and establish firm cell-cell adhesion. The E-cadherin cell adhesion system in cancer cells is inactivated by various mechanisms that reflect the morphological and biological characteristics of the tumor. Silencing of the E-cadherin gene by DNA hypermethylation around the promoter region occurs frequently, even in precancerous conditions. In diffuse infiltrating cancers, mutations are found in the genes for E-cadherin and alpha- and beta-catenins. At the invading front of cancers, the E-cadherin cell adhesion system is inactivated by tyrosine phosphorylation of beta-catenin; an oncogene product, c-erbB-2 protein, is found to associate directly with beta-catenin. The E-cadherin cell adhesion system cross-talks with the Wingless/Wnt signaling pathway through beta-catenin, and expression of genes, which participate in cancer morphogenesis, may be regulated in conjunction with the Wingless/Wnt signaling pathway. Dysadherin, a newly identified cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. In conclusion, inactivation of the E-cadherin cell adhesion system by both genetic and epigenetic mechanisms plays a significant role during multistage human carcinogenesis.

Fibroblast immortality is a prerequisite for transformation by EJ c-Ha- ras oncogene

Abstract: The established mouse cell line NIH 3T3 has been used with considerable success over the past three years as the basis of an in vitro transformation assay for demonstrating the presence of transfectable transforming genes in the DNA of certain human and rodent tumour cells (for review see ref. 1). In the case of the human bladder carcinoma cell lines EJ and T24, this approach has led2–4 to the molecular cloning of a transforming gene which is closely related to the rat-derived Harvey sarcoma virus oncogene, v-Ha-ras5,6. A single point mutation, which distinguishes these genes from their normal human homologue (c-Ha-ras1), is thought to be solely responsible for their transforming potential7–10. However, carcinogenesis in both humans and laboratory rodents is a multi-stage process (reviewed in ref. 11) of which the NIH 3T3 cell, already partly transformed, may represent only the penultimate stage. We therefore chose to examine the transforming effects of the EJ oncogene in a hamster fibroblast system originally developed in our laboratory to study stages in carcinogen-induced malignant transformation of normal diploid cells12. We show here that EJ c-Ha-ras-1 lacks complete transforming activity when transfected into normal fibroblasts which have a limited life-span, but can fully transform fibroblasts that have been newly ‘immortalized’ by carcinogens.