The role of Smad7 in oral mucositis

Abstract

Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. Among cancer patients, at least 40% and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation, develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenges for oral mucositis treatment are to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Oral mucositis is the result of complex, multifaceted pathobiology, involving a series of signaling pathways and a chain of interactions between the epithelium and submucosa. Among those pathways and interactions, the activation of nuclear factor-kappa B (NF-κB) is critical to the inflammation process of oral mucositis. We recently found that activation of TGFβ (transforming growth factor β) signaling is associated with the development of oral mucositis. Smad7, the negative regulator of TGFβ signaling, inhibits both NF-κB and TGFβ activation and thus plays a pivotal role in the prevention and treatment of oral mucositis by attenuating growth inhibition, apoptosis, and inflammation while promoting epithelial migration. The major objective of this review is to evaluate the known functions of Smad7, with a particular focus on its molecular mechanisms and its function in blocking multiple pathological processes in oral mucositis.

Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling

“…TGF-␤ signaling is finely controlled both in strength and in duration in normal contexts and is deregulated in a variety of human diseases (1,3,5,7,8,13). Smad7, an inhibitory Smad, has been found to play a vital role in restricting TGF-␤ signaling (15,24,25,29). It has been reported to exert inhibitory effects at the receptor level or the transcription level (1,8,15).…”

“…Consistent with its important function, altered expression of Smad7 has been associated with inflammatory bowel disease or tissue fibrosis, wherein low or high activity of TGF-␤ signaling is observed, respectively (28 -30). Moreover, Smad7 is highly expressed in several cancers, such as colorectal, pancreatic, skin, breast, liver, and prostate cancers and either inhibits or promotes cancer development depending on cancer types and contexts (23)(24)(25)(26)29).…”

Chemotherapy: oral side effects and dental interventions. A review of the literature

“…[23] The hematopoiesis resolves, the inflammation resolves, and the stromal fibroblasts are remodeled. [25] Mucositis is at its peak at 7-10 days after chemotherapy. Its first sign is erythema, followed by a burning sensation.…”

miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition

“…The Smad7 gene, also known as mothers against decapentaplegic homolog 7 (MADH7), is located on human chromosome 18q21.1 and encodes a protein of 426 amino acids [9]. Smad7-dependent activation of TGFβ signaling is able to induce the epithelial to mesenchymal transition (EMT) in CRC, allowing CRC cells to leave the tissue parenchyma and enter systemic circulation, followed by tumor invasion and metastasis [10].…”