SCF/c-KIT Signaling Increased Mucin2 Production by Maintaining Atoh1 Expression in Mucinous Colorectal Adenocarcinoma

Abstract

Mucinous colorectal adenocarcinoma (MCA) patients often a show high risk of malignant potential and a poorer survival rate. Given that the pathological feature and oncobiological characteristics of MCA are correlated with its abundant extracellular mucin2 (MUC2), we paid interest toward investigating the key factor that promotes MUC2 production exposure to highly-activated stem cell factor (SCF)/c-KIT signaling, which we believed to contribute to MCA formation. Long-term azoxymethane and dextran sodium sulfate treatment successfully induced MCA only in wild-type (WT) mice at week 37 and 43, while all c-kit loss-of-function mutant mice (Wadsm/m) developed non-MCA. Significantly, MUC2 and its key transcriptional factor Atonal homologue 1 (Atoh1) were remarkably expressed in MCA mice compared with non-MCA mice. Atoh1 was significantly elevated in colorectal cancer (CRC) cells stimulated by exogenous SCF or overexpressing c-KIT in vitro, while decreased by the blockage of SCF/c-KIT signaling with Imatinib. Furthermore, the maintained Atoh1 protein level was due to the inactive glycogen synthase kinase 3β (p-GSK3β) by virtue of the activated SCF/c-KIT-Protein Kinase B (AKT) signaling. Similar results were obtained from the ONCOMINE database and CRC patients. In conclusion, we suggested that SCF/c-KIT signaling promoted MUC2 production and MCA tumorigenesis by maintaining Atoh1 expression. Therefore, targeting the related key molecules might be beneficial for treating MCA patients.

Integrating scRNA-seq and bulk RNA-seq to characterize infiltrating cells in the colorectal cancer tumor microenvironment and construct molecular risk models

“…ATOH1 regulates intestinal progenitors downstream of Notch signaling and activates MUC2 transcription in goblet cells [40,41]. It was found that SCF/c-KIT signaling promotes the production of MUC2 and Mucinous Colorectal Adenocarcinoma (MCA) tumorigenesis by maintaining the expression of ATOH1 [42]. CXXC5, also known as retinoid-induced nuclear factor, belongs to the CXXC zinc-finger protein family [43].…”

Gene Expression Profile Reveals a Prognostic Signature of Non–MSI-H/pMMR Colorectal Cancer

“…Besides, EPHB2 mutations are closely associated with tumor suppression in gastric cancer and involved in the prognosis and metastasis of other tumors such as Ewing sarcoma ( Davalos et al, 2007 ; Keskin et al, 2021 ). ATOH1 is a target of the JNK1 and MUC2 pathways and closely associated with the proliferation, invasion, and metastasis of CRC cells ( Shen et al, 2018 ). HACL1 is closely related to small-cell lung cancer, and ERICH3 may be a key biomarker in nasopharyngeal carcinoma ( Owonikoko et al, 2014 ; Zhang et al, 2019 ).…”

Diverse expression patterns of mucin 2 in colorectal cancer indicates its mechanism related to the intestinal mucosal barrier

“…The expression of MUC2 in CRC tissues is reported to be related to the histopathological types of CRC. The expression of MUC2 in mucinous adenocarcinoma is increased, while that in non-mucinous adenocarcinoma is decreased[ 8 , 20 ]. In this study, patients with mucinous adenocarcinoma tended to have a higher proportion of patients with high expression of MUC2 than those with non-mucinous adenocarcinoma.…”