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Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers.

Sandoval-Bórquez A, Saavedra K, Carrasco-Avino G, Garcia-Bloj B, Fry J, Wichmann I, Corvalán AH - Dis. Markers (2015)

Bottom Line: The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics.Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics.Potential biomarkers are appearing from analyses of noncoding genomics.

View Article: PubMed Central - PubMed

Affiliation: Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile ; Scientific and Technological Bioresource Nucleus (BIOREN) and Graduate Program in Applied Cell and Molecular Biology, Universidad de La Frontera, 4811230 Temuco, Chile ; UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile.

ABSTRACT
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

No MeSH data available.


Related in: MedlinePlus

Canonical pathway of miRNA biogenesis in human. miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcript, called primary miRNA (pri-miRNA), which consists in a stem, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein exportin 5 (EXP5) and GTP-binding nuclear protein RAN-GTP. Subsequently, pre-miRNAs are cleaved by a ternary complex formed by Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes (miRNA-miRNA∗). Next, these are loaded onto an Argonaute protein (AGO) to form an immature RNA-Induced Silencing Complex (RISC) or pre-RISC, in a process mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of 6 to 8 base pairs of the miRNA, with a specific sequence of the target resulting in the gene silencing.
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Related In: Results  -  Collection


getmorefigures.php?uid=PMC4563069&req=5

fig4: Canonical pathway of miRNA biogenesis in human. miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcript, called primary miRNA (pri-miRNA), which consists in a stem, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein exportin 5 (EXP5) and GTP-binding nuclear protein RAN-GTP. Subsequently, pre-miRNAs are cleaved by a ternary complex formed by Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes (miRNA-miRNA∗). Next, these are loaded onto an Argonaute protein (AGO) to form an immature RNA-Induced Silencing Complex (RISC) or pre-RISC, in a process mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of 6 to 8 base pairs of the miRNA, with a specific sequence of the target resulting in the gene silencing.

Mentions: Small ncRNAs (sncRNAs) are represented by PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). piRNAs are specialized for repression of mobile elements and other genetic elements in germ line cells (e.g., LINE1 piRNAs and piR-823) [74, 75]. piRNAs and their associated proteins PIWI have been reported as deregulated in various tumor types and associated with the carcinogenic process [71]. siRNAs regulate posttranscriptional gene silencing and the defense against pathogen nucleic acids (e.g., L1-specific siRNA and oocyte endo-siRNAs) [76, 77] (Table 2). Therefore, they seem to have great potential in disease treatment, especially in the silencing of oncogenes [73]. miRNAs were discovered in the decade of 90s by Lee et al. [78] that were studying the fetal development of Caenorhabditis elegans. The investigation revealed that lin-4 gene was responsible of control of various developmental phases of the nematode. Interestingly, instead of encoding for a protein, this gene was transcribed into a short string of noncoding RNA that regulated another gene called lin-14 [78]. To date, more than 30,000 miRNAs have been found in over 200 species [79]. In humans, the latest miRNA database miRBase release (v21, June 2014, http://www.mirbase.org/) contains 2,588 annotated mature miRNAs. It is estimated that 60% of coding genes may be regulated by miRNAs. MicroRNAs are defined as small (~22 nt) noncoding RNAs, highly conserved, involved in the posttranscriptional regulation of gene expression in multicellular organisms [80]. Most miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcripts, called primary miRNAs (pri-miRNAs) [81]. A typical pri-miRNA consists of a stem of 33–35 bp, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. In the miRNA maturation process, two steps of cleavage take place. The first cleavage is performed in the nucleus by the Microprocessor complex (RNA III endonuclease, Drosha and DGCR8 cofactor) by cropping the stem-loop to release a small hairpin-shaped RNA of ~65 nucleotides in length, called precursor miRNA (pre-miRNA). Following Drosha processing, pre-miRNAs are exported into the cytoplasm by the protein exportin 5 (EXP5) forming a transport complex with GTP-binding nuclear protein RAN-GTP [82]. Upon export to the cytoplasm, pre-miRNAs are cleaved for the second time, by a ternary complex formed by RNase III endonuclease Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes about 22 nt in length [83]. The miRNA-miRNA∗ duplexes are made up by a “guide strand” and a “passenger strand” (miRNA∗). Selection of the guide strand depends on the relative thermodynamic stability of the first 1–4 bases at each end of the small RNA duplex [84]. Subsequently these are loaded onto an Argonaute protein (AGO 1–4) to form an immature RNA-induced Silencing Complex (RISC) or pre-RISC in a process ATP dependent mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex [85]. AGO proteins separate the two strands either via passenger-strand cleavage or through the aid of internal mismatches to generate a mature RISC effector [86]. Finally, activated RISC binds the target mRNA through complementary binding of 6 to 8 base pairs at the 5′ region of the miRNA guide strand (seed region), with a specific sequence of the 3′ region (3′UTR) of the target mRNA [87]. This affects both the stability and translation of messenger RNAs, resulting in downregulation of gene expression [20] (Figure 4). The biogenesis and function of miRNAs are under tight genetic and epigenetic control, including DNA methylation [88, 89]. Their deregulation is associated with many human diseases, particularly cancer [90, 91]. Oncogenic processes such as cell proliferation, differentiation, migration, and invasion are regulated by miRNAs [55]. This role has been associated not only with their binding to target genes, but also with the disruption of physiological expression patterns [91]. An example of this is the disruption of feedback loops between miRNAs and their target genes [92]. In gastric cancer cells, miR-139 could inhibit Jun expression by targeting a conserved site on its 3′-UTR, whereas Jun could induce miR-139 expression in a dose dependent manner through a distant upstream regulatory element which colocalizes spatially to miR-139 locus [93]. Functional analysis showed that restored expression of miR-139 significantly induces apoptosis and inhibits cell migration and proliferation as well as tumor growth through targeting Jun [93].


Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers.

Sandoval-Bórquez A, Saavedra K, Carrasco-Avino G, Garcia-Bloj B, Fry J, Wichmann I, Corvalán AH - Dis. Markers (2015)

Canonical pathway of miRNA biogenesis in human. miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcript, called primary miRNA (pri-miRNA), which consists in a stem, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein exportin 5 (EXP5) and GTP-binding nuclear protein RAN-GTP. Subsequently, pre-miRNAs are cleaved by a ternary complex formed by Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes (miRNA-miRNA∗). Next, these are loaded onto an Argonaute protein (AGO) to form an immature RNA-Induced Silencing Complex (RISC) or pre-RISC, in a process mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of 6 to 8 base pairs of the miRNA, with a specific sequence of the target resulting in the gene silencing.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4563069&req=5

fig4: Canonical pathway of miRNA biogenesis in human. miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcript, called primary miRNA (pri-miRNA), which consists in a stem, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein exportin 5 (EXP5) and GTP-binding nuclear protein RAN-GTP. Subsequently, pre-miRNAs are cleaved by a ternary complex formed by Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes (miRNA-miRNA∗). Next, these are loaded onto an Argonaute protein (AGO) to form an immature RNA-Induced Silencing Complex (RISC) or pre-RISC, in a process mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of 6 to 8 base pairs of the miRNA, with a specific sequence of the target resulting in the gene silencing.
Mentions: Small ncRNAs (sncRNAs) are represented by PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). piRNAs are specialized for repression of mobile elements and other genetic elements in germ line cells (e.g., LINE1 piRNAs and piR-823) [74, 75]. piRNAs and their associated proteins PIWI have been reported as deregulated in various tumor types and associated with the carcinogenic process [71]. siRNAs regulate posttranscriptional gene silencing and the defense against pathogen nucleic acids (e.g., L1-specific siRNA and oocyte endo-siRNAs) [76, 77] (Table 2). Therefore, they seem to have great potential in disease treatment, especially in the silencing of oncogenes [73]. miRNAs were discovered in the decade of 90s by Lee et al. [78] that were studying the fetal development of Caenorhabditis elegans. The investigation revealed that lin-4 gene was responsible of control of various developmental phases of the nematode. Interestingly, instead of encoding for a protein, this gene was transcribed into a short string of noncoding RNA that regulated another gene called lin-14 [78]. To date, more than 30,000 miRNAs have been found in over 200 species [79]. In humans, the latest miRNA database miRBase release (v21, June 2014, http://www.mirbase.org/) contains 2,588 annotated mature miRNAs. It is estimated that 60% of coding genes may be regulated by miRNAs. MicroRNAs are defined as small (~22 nt) noncoding RNAs, highly conserved, involved in the posttranscriptional regulation of gene expression in multicellular organisms [80]. Most miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic, or polycistronic loci to long primary transcripts, called primary miRNAs (pri-miRNAs) [81]. A typical pri-miRNA consists of a stem of 33–35 bp, a terminal loop, and single-stranded RNA segments at both the 5′- and 3′-UTR sides. In the miRNA maturation process, two steps of cleavage take place. The first cleavage is performed in the nucleus by the Microprocessor complex (RNA III endonuclease, Drosha and DGCR8 cofactor) by cropping the stem-loop to release a small hairpin-shaped RNA of ~65 nucleotides in length, called precursor miRNA (pre-miRNA). Following Drosha processing, pre-miRNAs are exported into the cytoplasm by the protein exportin 5 (EXP5) forming a transport complex with GTP-binding nuclear protein RAN-GTP [82]. Upon export to the cytoplasm, pre-miRNAs are cleaved for the second time, by a ternary complex formed by RNase III endonuclease Dicer, TAR RNA Binding Protein (TRBP), and Protein Activator of PKR (PACT), producing small RNA duplexes about 22 nt in length [83]. The miRNA-miRNA∗ duplexes are made up by a “guide strand” and a “passenger strand” (miRNA∗). Selection of the guide strand depends on the relative thermodynamic stability of the first 1–4 bases at each end of the small RNA duplex [84]. Subsequently these are loaded onto an Argonaute protein (AGO 1–4) to form an immature RNA-induced Silencing Complex (RISC) or pre-RISC in a process ATP dependent mediated for Heat shock cognate 70- (Hsc70-) Heat shock protein (Hsp90) chaperone complex [85]. AGO proteins separate the two strands either via passenger-strand cleavage or through the aid of internal mismatches to generate a mature RISC effector [86]. Finally, activated RISC binds the target mRNA through complementary binding of 6 to 8 base pairs at the 5′ region of the miRNA guide strand (seed region), with a specific sequence of the 3′ region (3′UTR) of the target mRNA [87]. This affects both the stability and translation of messenger RNAs, resulting in downregulation of gene expression [20] (Figure 4). The biogenesis and function of miRNAs are under tight genetic and epigenetic control, including DNA methylation [88, 89]. Their deregulation is associated with many human diseases, particularly cancer [90, 91]. Oncogenic processes such as cell proliferation, differentiation, migration, and invasion are regulated by miRNAs [55]. This role has been associated not only with their binding to target genes, but also with the disruption of physiological expression patterns [91]. An example of this is the disruption of feedback loops between miRNAs and their target genes [92]. In gastric cancer cells, miR-139 could inhibit Jun expression by targeting a conserved site on its 3′-UTR, whereas Jun could induce miR-139 expression in a dose dependent manner through a distant upstream regulatory element which colocalizes spatially to miR-139 locus [93]. Functional analysis showed that restored expression of miR-139 significantly induces apoptosis and inhibits cell migration and proliferation as well as tumor growth through targeting Jun [93].

Bottom Line: The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics.Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics.Potential biomarkers are appearing from analyses of noncoding genomics.

View Article: PubMed Central - PubMed

Affiliation: Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile ; Scientific and Technological Bioresource Nucleus (BIOREN) and Graduate Program in Applied Cell and Molecular Biology, Universidad de La Frontera, 4811230 Temuco, Chile ; UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile.

ABSTRACT
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

No MeSH data available.


Related in: MedlinePlus