Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy

Abstract

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is a complicated and often fatal cancer, and is related to a high disease-related mortality. Around 90% of mortalities are caused by the metastasis of CRC. Current treatment statistics shows a less than 5% 5-year survival for patients with metastatic disease. The development and metastasis of CRC involve multiple factors and mechanisms. The Hedgehog (Hh) signaling plays an important role in embryogenesis and somatic development. Abnormal activation of the Hh pathway has been proven to be related to several types of human cancers. The role of Hh signaling in CRC, however, remains controversial. In this review, we will go through previous literature on the Hh signaling and its functions in the formation, proliferation, and metastasis of CRC. We will also discuss the potential of targeting Hh signaling pathway in the treatment, prognosis, and prevention of CRC.

Keywords: Hedgehog signaling pathway; cancer therapy; colorectal cancer.

Figure 1

The sketch of Hedgehog (Hh) signaling pathway. The Hh signaling pathway contains three Hh homologs: Sonic Hh, Indian Hh, and Desert Hh. (A) When the ligand is absent (“Off” state), the patched (Ptc) receptor inhibits the downstream protein Smoothened (SMO). Henceforth, glioma-associated oncogene homolog (Gli) proteins are sequestered by Suppressor of Fused (SuFu). The Hh pathway is, generally, inhibited at “Off” state. (B) After activation of the Hh ligand, Hh proteins are released from the signaling cell. Hh then subsequently binds (“On” state) to PtcH, removing the inhibition and further activating SMO. SMO then regulates the downstream transduction molecules of Gli proteins (Gli1, Gli2, and Gli3). Gli proteins are subsequently transferred to the nuclei and they exert their transduction functions.