Goblet cell differentiation in colorectal cancer

Thesis

Disruption of goblet cell differentiation, resulting in reduced numbers of goblet cells is one of the major features of colorectal cancer (CRC). Therefore, investigating the regulatory mechanisms associated with goblet cell differentiation is important for a better understanding of CRC and finding new approaches to its prevention and treatment.

The Cancer and Immunogenetics laboratory own a large collection of CRC cell lines, which have been thoroughly examined regarding gene expression and mutation analyses. We assessed MUC2 and TFF3 protein expression levels in 100 CRC cell lines and categorised them into 5 distinct groups. These groups included high, medium, and low MUC2/TFF3-expressing cell lines, cell lines with no/very low MUC2 but high TFF3 expression, and cell lines completely lacking these proteins. MUC2-negative and TFF3-positive cell lines are novel CRC types that have not been described before.

While tracking goblet cell differentiation, we detected that TFF3 is expressed earlier than MUC2, possibly due to its faster folding and low molecular weight. It is also needed for holding mucin together during secretion. The proportion of MUC2/TFF3-positive cells was much higher in single-derived LS180 colonies compared to bulk culture.

We also investigated the effects of the main transcription factors on goblet cell differentiation. Downregulation of ATOH1, SPDEF, CDX1, and CDX2 led to a significant reduction in MUC2/TFF3-positive cells in multiple CRC cell lines. Among these factors, ATOH1 had a more substantial effect compared to others. But it is still not enough to induce MUC2/TFF3 expression in completely negative CRC cell lines. Suppression of methylation had variable effects on different CRC cell lines. We suggest that in the group 4 cell lines, MUC2 is most likely methylated as opposed to other group cell lines that might be regulated by demethylation of transcription factors, such as ATOH1 and HES1.

Authors: Abdullayeva, G

• DOI: 10.5287/ora-8gwmbq2xz
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cell differentiation; goblet cell; colorectal cancer; transcription factors
• Subjects: Oncology