The role of oncogenes in gastrointestinal cancer

Abstract

Oncogene research over the last century has been one of the major advances in understanding the molecular biology of malignant disease. Oncogenes are a structurally and functionally heterogeneous group of genes, whose protein products act pleiotropically and affect multiple complex regulatory cascades within the cell. They regulate cell proliferation, growth, and differentiation, as well as control of the cell cycle and apoptosis. The products of oncogenes include growth factors, growth factor receptors, signal transducers, transcription factors, and apoptosis regulators, as well as chromatin remodelers. Several distinct mechanisms have been described for the conversion of proto-oncogenes to active oncogenes. Quantitative forms of oncogene activation include multiplication (gene amplification) or translocation to an active chromatin domain that brings a growth-regulatory gene under the control of a different promoter, causing inappropriate expression of the gene. Qualitative forms include either point mutations or the production of a novel product from a chimeric gene. Further understanding of the molecular mechanisms by which oncogenes regulate normal development and tumorigenesis may lead to novel concepts in the diagnosis and treatment of cancer in humans. In this review, we focus on the role of selected oncogenes in gastrointestinal cancer.

Figure 1.

Simplified schematic version of the epidermal growth factor receptor (EGFR) signaling cascade. Stimulation of EGFR by ligands such as epidermal growth factor (EGF) or transforming growth factor-α (TGF-α) results in dimerization and phosphorylation of the receptor. This triggers activation of K-ras through the small adaptor proteins Grb2 and Sos. K-ras functions as the central distributor of the signal via both phospho-inositol kinases (P3K) and BRAF. PI3K inhibits apoptosis through AKT activation, while BRAF stimulates cell growth and proliferation through the mitogen-activated protein kinase (MAPK) pathway. The BRAF kinase is downstream of K-ras, and this explains why wild-type status of both K-ras and BRAF are necessary for EGFR blockade to work.

Figure 2.

Model of c-myc/Max and Mxd/Max in transcriptional regulation. Proteins of the myc/Mxd/Mad network possess a C-terminal basic region/helix-loop-helix/leucine zipper domain (bHLHLZ), which specifies dimerization within the network and determines sequence-specific DNA binding. The c-myc/max heterodimer binds to the E box 5′-CACGCG-3′ and activates the transcription of genes involved in proliferation, differentiation, quiescence, and apoptosis. Transcriptional activation by c-myc is antagonized by Mxd, which also binds to Max. The Mad/Mxd dimers can bind the same E-boxes and repress transcription. Adapted from Calcagno DQ, et al: MYC and gastric adenocarcinoma carcinogenesis, World J Gastroenterol 14(39):5963, 2008.

Figure 3.

The KIT receptor tyrosine kinase. (A) C-KIT mutations occur in 80–90% of GISTs. Mutations of c-KIT in the juxtamembrane (JM) domain in gastrointestinal stromal tumors (exon 11) are found in approximately 65% of cases. Mutations also occur in the extracellular (EC) domains (exons 8, 9) and in the phosphokinase (TK1, TK2) domains (exons 13, 17), which are split by a structure of kinase insert (KI). (B) Dimerization, phosphorylation (P), and activation of the normal c-KIT receptor by its ligand stem-cell factor (SCF) are shown. (C) Imatinib mesylate, a small-molecule selective inhibitor of the KIT tyrosine kinase, is a competitive antagonist of the adenosine triphosphate binding site. It therefore blocks receptor phosphorylation and activation. Modified from Hirota S, Isozaki K: Pathology of gastrointestinal stromal tumors, Pathol Int, 56(1):3, 2006.

Figure 4.

Cyclin D1 controls the G₁–S-phase transition through interactions with the retinoblastoma protein (RB). Cyclin D1 heterodimerizes with cyclin-dependent kinases (CDKs) 4 and 6, respectively, to inactivate the tumor suppressor RB by phosphorylation. Active RB functions as a repressor of E2F transcription factors, whereas inactivation (phosphorylation) of RB allows their release. E2F transcription factors activate the transcription of genes that are involved in the G₁-to-S phase transition and cell-cycle progression.

Figure 5.

Synthesis of microRNAs. MicroRNA (miRNA) is transcribed by RNA polymerase (pol) II into long primary miRNA (pri-miRNA), which are processed in the nucleus by the RNase III enzyme Drosha, resulting in a smaller hairpin precursor form called named premiRNA. PremiRNA binds exportin 5 and is transported to the cytoplasm, where it is cleaved by another RNase enzyme called Dicer into mature miRNA. Mature miRNA is incorporated into a large protein complex called RISC (RNA-induced silencing complex) and depending on the degree of complimentarity with the target mRNA induces translational repression or mRNA degradation. Adapted from Garzon R, et al: MicroRNA expression and function in cancer, Trends Mol Med, 12(12):581, 2006.