Critical interactions between TGF-beta signaling/ELF, and E-cadherin/beta-catenin mediated tumor suppression.
Inactivation of the transforming growth factor-beta (TGF-beta) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf+/- and elf+/- / Smad4+/- mutant mice. We found that embryonic liver fodrin (ELF), a beta-Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell-cell contacts and E-cadherin-beta-catenin-dependent epithelial cell-cell adhesion is disrupted in elf+/- / Smad4+/- mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF-beta stimulation. In contrast, elf+/- / Smad4+/- mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF-beta signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.
Katuri
V
V
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.|Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
Tang
Y
Y
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.|Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
Li
C
C
Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA.
Jogunoori
W
W
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
Deng
C-X
CX
Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA.
Rashid
A
A
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sidawy
A N
AN
Department of Surgery, Washington, DC, USA.|Department of Veterans Affairs, Washington, DC, USA.
Evans
S
S
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
Reddy
E P
EP
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
Mishra
B
B
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.
Mishra
L
L
Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA.|Department of Surgery, Washington, DC, USA.|Department of Veterans Affairs, Washington, DC, USA.
D000818:Animals; D015820:Cadherins / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000502:physiology; D002448:Cell Adhesion; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000503:physiopathology; D020869:Gene Expression Profiling; D051379:Mice; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology; D013049:Spectrin
D015820:Cadherins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D013049:Spectrin; C490810:Smad4 protein, mouse