SCF/c-KIT signaling promotes mucus secretion of colonic goblet cells and development of mucinous colorectal adenocarcinoma

Guilan Li; Shu Yang; Ping Shen; Bo Wu; Tingyi Sun; Haimei Sun; Fengqing Ji; Deshan Zhou

SCF/c-KIT signaling promotes mucus secretion of colonic goblet cells and development of mucinous colorectal adenocarcinoma

Am J Cancer Res. 2018 Jun 1;8(6):1064-1073. eCollection 2018.

Authors

Guilan Li¹, Shu Yang^{1

2

3}, Ping Shen¹, Bo Wu^{1

2

3}, Tingyi Sun^{1

2

3}, Haimei Sun^{1

2

3}, Fengqing Ji¹, Deshan Zhou^{1

2

3}

Affiliations

¹ Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University Beijing 100069, P. R. China.
² Beijing Key Laboratory of Cancer Invasion and Metastasis Research Beijing 100069, P. R. China.
³ Cancer Institute of Capital Medical University Beijing 100069, P. R. China.

PMID: 30034943
PMCID: PMC6048403

Abstract

Mucinous colorectal adenocarcinoma (MCA) is characterized by a great mount of extracellular mucus fundamentally composed of Mucin2 (MUC2) which is significantly correlated with the high malignancy and strong invasive ability of MCA. However, rare is known about the underlying mechanism of the mucus accumulation in MCA. Our latest study demonstrated that SCF/c-KIT signaling was highly activated in MCA patients and mouse model, which up-regulated MUC2 transcription. In the present study, we paid a special interest in whether and how SCF/c-KIT signaling promoted mucus secretion by using wild-type (WT) C57BL mice and their littermates who harbor mutational c-kit gene (Wads^m/m), clinical colorectal cancer (CRC) samples, as well as human CRC cell lines. Our results clearly showed that the inner mucus layer of colon was thinner and the intracellular mucin residual was more in Wads^m/m mice than those in WT mice by Alcian blue and PAS staining, suggesting that the mucus secretion process was crippled when SCF/c-KIT signaling was hypo-activated. Inhibiting SCF/c-KIT signaling by Imatinib also resulted in weakened mucus secretion in WT mice. Intraperitoneal administration of MANS which competitively inhibits the activity of the vesicular transport protein MARCKS efficiently reduced mucus secretion in colonic goblet cells of WT mice. Significantly, phosphorylated MARCKS (p-MARCKS) was overtly decreased in colonic mucosa of Wads^m/m mice compared with WT mice, indicating that SCF/c-KIT signaling-regulated mucus secretion was probably mediated by MARCKS activation. Similar results were obtained in MCA patients and mouse model. Moreover, SCF/c-KIT signaling was activated or inhibited in HT-29 and LS174T CRC cells, which potently increased or decreased MARCKS activity, respectively. Finally, we found that PKCδ, a known kinase for MARCKS, was activated in WT and MCA mice along with MARCKS. Inhibition or activation of SCF/c-KIT signaling resulted in decreased or increased PKCδ activity respectively in vitro. In conclusion, we demonstrated that SCF/c-KIT signaling can promote the mucus secretion by activating PKCδ-MARCKS, which provided a new insight into understanding the mechanism of mucus secretion of goblet cells and MCA development.

Keywords: Goblet cell; MARCKS; c-KIT; mucinous colorectal adenocarcinoma; mucus secretion.