Gastric cancer (GC) is a major cause of cancer mortality. GC studies that aim to identify relevant oncogenes and tumor suppressor genes (TSGs) are essential for devising effective new therapies. A decade ago, RUNX3, a...Gastric cancer (GC) is a major cause of cancer mortality. GC studies that aim to identify relevant oncogenes and tumor suppressor genes (TSGs) are essential for devising effective new therapies. A decade ago, RUNX3, a gene that resides on human chromosome 1p36.1, was claimed to be a major TSG in GC. Since then, hundreds of studies involving thousands of GC patients have attempted to verify and extend the RUNX3 TSG paradigm. However, RUNX3 is not recognized as TSG and not listed in the “Cancer Gene Census” website. To be a TSG that protects normal cells against malignancy, the gene must be expressed in the normal tissue from which the cancer arose and its loss or inactivation should contribute to cancer development. This review summarizes compelling body of evidence challenging the RUNX3-TSG paradigm. Studies show unequivocally that RUNX3 is not expressed in normal gastric epithelium and that it fails to fulfill all other premises of a TSG. RUNX3 mutations and 1p36 deletions are not frequent in GC and RUNX3 is not associated with familial GC or with increased risk of GC. Accordingly, Runx3-/- mice do not develop tumors. RUNX3 promoter methylation, which has been reported to be a frequent event in GC, is not relevant to its alleged TSG function, since the gene is already silent in normal gastric epithelium. In sharp contrast, overexpression of RUNX3 was found in several types of human cancers, including GC, and the 1p36.1 region is amplified in B-cell lymphoma. Thus, it is possible that RUNX3 actually promotes cancer development rather than being a TSG. The true targets for GC therapy are discussed below. Those are genes frequently lost or amplified in GC and are well known for their tumor suppressive or oncogenic activity, respectively.展开更多
Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound ac...Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound active form and a GDP-bound inactive form.The activated RhoA directly interacts with its downstream effectors,such as Rho kinase(ROCK)to regulate actomyosin dynamics,or mDia1 to control stress fiber and filopodia formation.The activity of RhoA is primarily regulated by guanine nucleotide exchange factors(GEFs),GTPaseactivating protein(GAP),and guanine nucleotidedissociation inhibitors(GDIs).展开更多
miR-7正常表达在正常细胞和器官的生长、发育以及分化中发挥重要作用。在多种肿瘤细胞中,miR-7的表达下调,充当抑癌基因的角色。miR-7作为一种抑癌基因在多种肿瘤的发生和发展中发挥作用,与肿瘤增殖、迁移及侵袭等行为密切相关。miR-7...miR-7正常表达在正常细胞和器官的生长、发育以及分化中发挥重要作用。在多种肿瘤细胞中,miR-7的表达下调,充当抑癌基因的角色。miR-7作为一种抑癌基因在多种肿瘤的发生和发展中发挥作用,与肿瘤增殖、迁移及侵袭等行为密切相关。miR-7的表达受细胞内多种信号通路的调控,如Yin Yang 1、Paired box 6、TYRO3等,通过调控与miR-7相关的信号通路可为结直肠癌的诊治提供新思路。miR-7具有良好的临床应用前景,可为将来更好地治疗结直肠癌提供新途径。展开更多
文摘Gastric cancer (GC) is a major cause of cancer mortality. GC studies that aim to identify relevant oncogenes and tumor suppressor genes (TSGs) are essential for devising effective new therapies. A decade ago, RUNX3, a gene that resides on human chromosome 1p36.1, was claimed to be a major TSG in GC. Since then, hundreds of studies involving thousands of GC patients have attempted to verify and extend the RUNX3 TSG paradigm. However, RUNX3 is not recognized as TSG and not listed in the “Cancer Gene Census” website. To be a TSG that protects normal cells against malignancy, the gene must be expressed in the normal tissue from which the cancer arose and its loss or inactivation should contribute to cancer development. This review summarizes compelling body of evidence challenging the RUNX3-TSG paradigm. Studies show unequivocally that RUNX3 is not expressed in normal gastric epithelium and that it fails to fulfill all other premises of a TSG. RUNX3 mutations and 1p36 deletions are not frequent in GC and RUNX3 is not associated with familial GC or with increased risk of GC. Accordingly, Runx3-/- mice do not develop tumors. RUNX3 promoter methylation, which has been reported to be a frequent event in GC, is not relevant to its alleged TSG function, since the gene is already silent in normal gastric epithelium. In sharp contrast, overexpression of RUNX3 was found in several types of human cancers, including GC, and the 1p36.1 region is amplified in B-cell lymphoma. Thus, it is possible that RUNX3 actually promotes cancer development rather than being a TSG. The true targets for GC therapy are discussed below. Those are genes frequently lost or amplified in GC and are well known for their tumor suppressive or oncogenic activity, respectively.
基金supported in part by R01-CA140571,P01 CA116676,Anise McDaniel Brock Scholar fund to WZ,1R01CA142858 to AM,and P30CA138292 to Winship Cancer Institute。
文摘Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound active form and a GDP-bound inactive form.The activated RhoA directly interacts with its downstream effectors,such as Rho kinase(ROCK)to regulate actomyosin dynamics,or mDia1 to control stress fiber and filopodia formation.The activity of RhoA is primarily regulated by guanine nucleotide exchange factors(GEFs),GTPaseactivating protein(GAP),and guanine nucleotidedissociation inhibitors(GDIs).
文摘miR-7正常表达在正常细胞和器官的生长、发育以及分化中发挥重要作用。在多种肿瘤细胞中,miR-7的表达下调,充当抑癌基因的角色。miR-7作为一种抑癌基因在多种肿瘤的发生和发展中发挥作用,与肿瘤增殖、迁移及侵袭等行为密切相关。miR-7的表达受细胞内多种信号通路的调控,如Yin Yang 1、Paired box 6、TYRO3等,通过调控与miR-7相关的信号通路可为结直肠癌的诊治提供新思路。miR-7具有良好的临床应用前景,可为将来更好地治疗结直肠癌提供新途径。
