<p>KLHL22 Regulates the EMT and Proliferation in Colorectal Cancer Cells in Part via the Wnt/β-Catenin Signaling Pathway</p>

Abstract

Background: Colorectal cancer (CRC) is one of the most common aggressive malignancies. KLHL22 functions as a tumor suppressor, and previous findings have demonstrated that KLHL22 can regulate the development of breast cancer and CRC. However, few studies have investigated the role of KLHL22 in CRC cell epithelial-to-mesenchymal transition (EMT) and proliferation. The current study aimed to detect the role of KLHL22 in CRC cell proliferation and EMT and to elucidate the probable molecular mechanisms through which KLHL22 is involved with these processes. Materials and Methods: Transwell invasion, MTT, immunohistochemistry and Western blotting assays were performed to evaluate the migration, invasion and proliferation abilities of CRC cells, and the levels of active molecules involved in the Wnt/β-catenin signaling pathway were examined through Western blotting analysis. In addition, the in vivo function of KLHL22 was assessed using a tumor xenograft model. Results: KLHL22 expression was weaker in CRC tissues than in nonmalignant tissues and could inhibit cell invasion, migration, and proliferation in vitro. Furthermore, the regulatory effects of KLHL22 on EMT were partially attributed to the Wnt/β-catenin signaling pathway. The in vivo results also showed that KLHL22 modulated CRC tumorigenesis. Conclusion: KLHL22 can regulate the activity of GSK-3β to influence the level of PI3K, and this regulation promotes EMT inhibition partially through the Wnt/β-catenin signaling pathway.

Overexpression of KLHL22 correlates with poor prognosis in patients with triple-negative breast cancer

“…Overall, KLHL22 could be used as an independent prognostic factor to predict the overall and progression-free survival of patients with TNBC, as evidenced by our clinical data and expression studies. However, a study by Song et al ( 22 ) found that KLHL22 protein levels in clinicopathological tissue samples of patients were lower than those in normal tissues, and they further explained that KLHL22 acts as a tumor suppressor and regulates proliferation and epithelial-mesenchymal transition through the Wnt/β-catenin signaling pathway in colorectal cancer cells. In addition, Zhou et al ( 23 ) revealed that KLHL22 plays a crucial role in maintaining the programmed cell death protein 1 (PD-1) expression balance and preventing excessive suppression of T cells.…”

Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy

“… 86 Besides, KLHL22 can modulate the activity of GSK-3β to affect PI3K level via Wnt/β-catenin signaling pathway, further regulating the EMT process and cell proliferation in colorectal cancer. 87 A previous study has reported that KLHL22 can decrease the number of PD-1 located on the cell surface by promoting its ubiquitin degradation. Decreased KLHL22 contributes to the overaccumulation of PD-1, which inhibits the normal function of immune system and facilitates tumor development and progression.…”

The Wnt Signalling Pathway: A Tailored Target in Cancer

“…The kelch-like family member 22 ( KLHL22 ) is a tumour suppressor protein involved in the development/progression of several cancers [ 30 ]. Low expression of KLHL22 was found in CRC tissues.…”

“…KLHL22 overexpression was associated with decreased migration, invasion and reduced expression of the EMT markers, vimentin, N-cadherin, Twist1 and Snail1. Intriguingly, KLHL22 knockdown led to increased expression of β-catenin and LEF , while KLHL22 overexpression translates into GSK-3β upregulation and β-catenin downregulation [ 30 ] ( Table 1 ).…”