title: Smad4 suppresses the progression of renal cell carcinoma via the activation of forkhead box protein H1.
abstract: Smad4 has recently been identified as a tumor suppressor gene in a variety of cancers, yet the role of Smad4 in renal cell carcinoma (RCC) remained to be elusive. Therefore, the aim of the present study was to explore the function of Smad4 in RCC. The expression of Smad4 reduced the growth rate of RCC. The levels of Smad4 and forkhead box protein H1 (FOXH1) mRNA were reduced, while the levels of estrogen receptor were increased in RCC cells compared with those in human renal epithelial cells (P<0.01). Western blot analysis showed an identical trend among the three molecules. Glutathione S‑transferase pull‑down and immunoprecipitation assays proved the interaction between Smad4 and FOXH1. An immunofluorescence assay revealed that Smad4 and FOXH1 were colocalized in the nuclei of RCC cells. Smad4 interacts with Smad2 and migrates into the nucleus, where it interacts with FOXH1 to repress the protein expression of estrogen receptor. These results indicate that Smad4 acts as a tumor suppressor by activating FOXH1, and then suppressing the expression of estrogen receptor, in addition to tumor migration and invasion. Hence, Smad4 should be investigated as a potential target for the treatment for RCC.
authors.affiliation: Department of Urological Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Urological Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urological Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urological Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Zhaoyan
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; D011960:Receptors, Estrogen; D051901:Smad4 Protein