Hypoxic Conversion of SMAD7 Function from an Inhibitor into a Promoter of Cell Invasion

Abstract

Smad7 is an inhibitor of the transforming growth factor-β-activated signaling pathway. Under welloxygenated conditions, Smad7 is a potent inhibitor of carcinoma cell invasion. Paradoxically, however, the expression of Smad7 is upregulated across several cancers and may promote cancer progression. Hypoxia, which is frequently met in solid tumors, is an enhancer of carcinoma cell invasion and cancer progression. Here, we report that hypoxia activates the expression of Smad7 in a hypoxia-inducible factor-and von HippelLindau protein-dependent manner. As expected, in normoxia, the forced expression of Smad7 inhibited carcinoma cell invasion. In contrast with the normoxic condition, the inhibitory effect of Smad7 was lost under hypoxia. The block in carcinoma cell invasion by forced expression of Smad7 was released by hypoxia in two invasive carcinoma cell lines. Moreover, the noninvasive HaCaT keratinocytes become invasive upon simultaneous hypoxia and transforming growth factor-β stimulus. The hypoxia-activated invasion was attenuated by inhibiting Smad7 expression by short interfering RNA. Finally, the increased Smad7 expression in human carcinomas correlated with hypoxic gene expression. The data provide evidence that hypoxia could convert Smad7 function from an invasion inhibitor into an activator of invasion. Furthermore, they might shed light as to why increased Smad7 expression is detected in cancers. Cancer Res; 70(14); 5984-93. ©2010 AACR.

HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress

“…25 Taken together, our data show that loss of PHD2 in the HSC compartment leads to enhanced HIF1a-related proliferation of early MPP fractions, which might be directly related to a reduced activity of the TGFb pathway.…”

“…19 Furthermore, SMAD7 can be regulated by hypoxia in a HIF1a/pVHL-dependent manner. 25 Accordingly, mice double deficient for PHD2 and HIF1a show no difference in SMAD7 or p21 expression compared with their WT littermates.…”

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

“…19 Furthermore, hypoxia seems to shape the TGF-b1 response by differentially affecting specific SMAD proteins, which execute the transcriptional TGF-b1 response. 20,21 Our data add to the understanding of the cooperative nature of hypoxia and TGF-b1 related pathways by demonstrating the effects of PHD2 on TGF-b1 processing.…”

“…Previously it has been reported that SMAD7, which has an inhibitory function is increased in hypoxia, which might in addition at least in part explain the decrease in SMAD activity in the PHD2 knock down cells. 21 …”

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

“…reported that hypoxic conditions could convert SMAD7 function from an inhibitor into a promoter of cell invasion in cancer, which was supported by evidence that increased SMAD7 expression in human cancer correlated with hypoxic gene expression. Further studies are needed to better understand how SMAD7 functions during EMT and metastasis 36.…”