Some experimental studies have suggested that loss of Numb expression is associated with tumor behavior in CRC. In recent years, there has been evidence that aggressive tumor behavior in various solid tumors is associated with loss of Numb expression. Numb also increases mucin secretion in intestinal cells and helps to maintain the integrity of the epithelial barrier. Numb is expressed in many adult tissues, such as the breast, lung, testis, and salivary gland it is detected in the villus crypt axis in the mouse intestine and participates in goblet cell transformation by inhibiting the Notch pathway in intestinal epithelial cells. In addition, data obtained in recent years indicate that Siah-1 may also play a role in the degradation of β-catenin. Siah-1 has an inhibitory effect on Numb but a stimulatory effect on Notch-1. Furthermore, the networking of Numb into E3 ubiquitin ligase-based circuitries in the regulation of Notch signaling involves other E3 ubiquitin ligases, including seven in Siah-1.
Numb and Itch function in concert to promote ubiquitination of the Notch receptor before activation. Ubiquitination of the membrane-bound Notch receptor Notch-1 and subsequent attenuation of its activity are the basis of this molecular mechanism, which involves the binding of Numb to the E3 ubiquitin-ligase Itch. Numb is a conserved evolutionary protein that antagonizes Notch signaling activities in regulating the balance between proliferation and differentiation in development and homeostasis. However, differences in the findings of studies on its use in CRC as a therapeutic target exist, which necessitates an understanding of the roles of other components in the Notch pathway. In recent years, the role of the Notch signaling pathway in gastrointestinal development and normal gut homeostasis has been thoroughly demonstrated. In this context, numerous studies have been conducted to elucidate signaling pathways that contribute to colorectal tumor development and progression and to use them as potential therapeutic targets, mainly to prevent aggressive tumor behavior and treatment resistance.Īlthough Notch signaling has traditionally been known for its role in determining cell fate, its identification as one of the most active pathways in cancer cells renders it a potential therapeutic target in CRC. Although curative surgery is possible in some cases, the fact that one-fifth of patients have metastatic disease at the time of diagnosis and sixty percent of patients undergoing surgical resection experience recurrence and metastasis emphasizes the need to identify new strategies for the determination of CRC tumor behavior and treatment.
Colorectal carcinoma (CRC) is one of the most common cancers worldwide and, despite significant advances in treatment, ranks third in cancer-related mortality and morbidity.