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

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 14; pp. 5984 - 5993
• Main Authors: HEIKKINEN, Pekka T, NUMMELA, Marika, JOKILEHTO, Terhi, GRENMAN, Reidar, KÄHÄRI, Veli-Matti, JAAKKOLA, Panu M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2010
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Hypoxia - physiology; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Keratinocytes - metabolism; Male; Medical sciences; Middle Aged; Neoplasm Invasiveness; Pharmacology. Drug treatments; Phosphorylation; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Smad Proteins, Receptor-Regulated - antagonists & inhibitors; Smad Proteins, Receptor-Regulated - metabolism; Smad7 Protein - biosynthesis; Smad7 Protein - genetics; Smad7 Protein - metabolism; Tumors; Promoter; Oxygen; Hypoxia; Inhibitor; Malignant tumor; Metastasis; Cell; Conversion; In vitro; Invasion; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-3777

Smad7 is an inhibitor of the transforming growth factor-beta-activated signaling pathway. Under well-oxygenated 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 Hippel-Lindau 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-beta 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.