Molecular biological analysis of 5-FU-resistant gastric cancer organoids: KHDRBS3 contributes to the attainment of features of cancer stem cell

概要

学位論文

全文要約

Molecular biological analysis of 5-FU-resistant
gastric cancer organoids; KHDRBS3 contributes to
the attainment of features of cancer stem cell
（5-FU 耐性胃癌オルガノイドの分子生物学的解析;
KHDRBS3 は癌幹細胞性の獲得に寄与する）

主指導教員:安井
(医系科学研究科

弥教授

分子病理学)

副指導教員:武島

幸男教授

(医系科学研究科

病理学)

副指導教員:大上

直秀准教授

(医系科学研究科

分子病理学)

学位申請者

鵜飼

（医歯薬保健学研究科

翔一

医歯薬学専攻）

全文要約 (Abstract)
5-FU is one of the key drugs in the treatment of gastric cancer (GC). Much evidence has
shown that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance.
The organoid is a novel 3D cell culture system technology that sustains stem-cell-driven
formation of near-physiological, self-renewing tissues using specific niche factors in a
dish. In this study, we established GC organoids (GCOs) and gradually treated them
with higher concentrations of 5-FU. We successfully harvested four 5-FU-resistant
GCOs, which were supported by significant changes in the expression of molecules
related to 5-FU metabolism. We then performed microarray analysis using three normal
gastric organoids and three pairs of 5-FU-resistant and parental GCOs. Through the
comparison of expression profiles and further validation, we chose KHDRBS3 as a
target gene. We found KHDRBS3 to be an independent prognostic factor in GC patients,
especially in GC patients treated with 5-FU chemotherapy. We also determined that
KHDRBS3 might play an important role in the acquisition of stem cell-like features,
such as multi-drug resistance and organoid formation, by regulating CD44 variant
expression. We found KHDRBS3, which is thought to play an important role in the
acquisition of characteristics of CSCs in GC, to be a promising candidate marker for
predicting therapeutic effect and prognosis in GC patients.
Material from : Ukai, S., Honma, R., Sakamoto, N. et al. Molecular biological analysis of
5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of
features of cancer stem cell. Oncogene 39, 7265–7278 (2020).
https://doi.org/10.1038/s41388-020-01492-9
https://www.nature.com/articles/s41388-020-01492-9