Numb negatively regulates the epithelial-to-mesenchymal transition in colorectal cancer through the Wnt signaling pathway

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors and is associated with a high mortality rate due to the lack of specific biomarkers available for early diagnosis, targeted therapies, and prognostic surveillance. In the present study, we investigated the function of Numb and its underlying mechanism in CRC. Immunohistochemical staining and clinicopathological analysis were used to assess the expression of Numb and its clinical significance in patients with CRC. Quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays were used to investigate the function of Numb and its underlying mechanism in CRC. Numb expression was downregulated and negatively correlated with the depth of invasion, tumor size, metastasis, TNM stage, and epithelial-to-mesenchymal transition (EMT) markers in CRC specimens. Numb negatively regulates the EMT, proliferation, invasion, migration, and the Wnt signaling pathway in vitro, as well as tumor growth and metastasis in vivo. Furthermore, activation of the Wnt signaling pathway by Wnt-3A negated the effect of Numb overexpression, whereas inhibition of the Wnt signaling pathway by IWR-1 impaired the effect of the Numb knockdown on the EMT. We concluded that Numb downregulation is a common event in patients with CRC and is closely correlated with cancer progression and a poor prognosis. Numb functions as a tumor suppressor in CRC, and its tumor suppressor function is mediated by negative regulation of the EMT through the Wnt signaling pathway. NEW & NOTEWORTHY We investigate the function of Numb and its underlying mechanism in colorectal cancer through quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays. We conclude that Numb can negatively regulate the epithelial-to-mesenchymal transition through the Wnt signaling pathway to inhibit the development of colorectal cancer.

Differential Expression Analysis Revealing CLCA1 to Be a Prognostic and Diagnostic Biomarker for Colorectal Cancer

“…We used GO and KEGG enrichment analyses to explore the functions of the DEGs identified by overlapping the DEGs in the 3 datasets. GO analysis indicated that negative regulation of growth, bicarbonate transport, and transporter activity ( 38 – 40 ) were closely related to the development and growth of cancer; some KEGG pathways, such as nitrogen metabolism and retinol metabolism, were also linked to the pathogenesis of CRC. Nitrogen is an essential biomolecule in humans and regulates cellular metabolism, and retinol is a form of vitamin A closely related to immune functions ( 41 , 42 ).…”

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

“…A number of studies have shown that the Wnt signaling pathway contributes to increased invasion and malignancy of tumor cells via EMT induction [258][259][260]. The inhibition of Wnt by onco-suppressor factor Numb suppresses EMT in cancer cells, thereby illustrating the role of Wnt as an upstream mediator of EMT [261]. In addition, EMT induction by Wnt can elevate proliferation of cancer cells, and triggers their resistance into apoptosis [262].…”

UBE2S and UBE2C confer a poor prognosis to breast cancer via downregulation of Numb

“…Numb was widely reported as a tumor suppressor in various cancers, and low expression of Numb was related to highly malignant tumor cells ( 21 , 28 , 50 , 51 ). As shown in our data, there was reduced expression of Numb at the protein level, suggesting the involvement of ubiquitination and protein degradation ( 29 , 52 , 53 ).…”