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BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma.

ABSTRACT: Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274^low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274^low cells, and that BEX2 knockdown decreased the tumorigenicity and G₀ phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G₀ phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.

SUBMITTER: Tamai K

PROVIDER: S-EPMC7725823 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma.

Tamai Keiichi K Nakamura-Shima Mao M Shibuya-Takahashi Rie R Kanno Shin-Ichiro SI Yasui Akira A Mochizuki Mai M Iwai Wataru W Wakui Yuta Y Abue Makoto M Yamamoto Kuniharu K Miura Koh K Mizuma Masamichi M Unno Michiaki M Kawamura Sadafumi S Sato Ikuro I Yasuda Jun J Yamaguchi Kazunori K Sugamura Kazuo K Satoh Kennichi K

Scientific reports 20201209 1

Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expres ...[more]

PMID: 33299012

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Project description:BackgroundIntrahepatic cholangiocarcinoma (ICC) is a highly invasive bile duct cancer with poor prognosis due to frequent recurrence and limited effective treatments. Cancer stem cells (CSCs) contribute to ICC's therapeutic resistance and recurrence, driven by distinct cellular subpopulations with variable tumorigenic properties. Recent advances in single-cell RNA sequencing (scRNA-seq) have enabled a deeper exploration of cellular heterogeneity in tumors, offering insights into unique CSC subgroups that impact ICC progression and patient outcomes. This study aimed to investigate the effect of CSC heterogeneity on the prognosis of ICC.MethodsThe scRNA-seq dataset GSE142784 was retrieved from the Gene Expression Omnibus (GEO) database, and Bulk RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) databases. Hallmarks and AUCell R package were adopted for analyzing the signaling pathway activity, CellChat for observing cell communication between subgroups, and SCENIC for analyzing transcription factors expression. The immune cell infiltration and drug sensitivity of the model were analyzed using the CIBERSORT algorithm and the "pRRophetic" R packages, respectively. And immunohistochemistry (IHC) tests were used to evaluate expression of transcription factors in ICC patients.ResultsBased on scRNA-seq data, five clusters (DLK+, CD13+, CD90+, CD133+, and other cholangiocarcinoma cells) were observed in ICC, which presented different signaling pathway activities, such as HSF1 and STAT1 were highly expressed in the CD133 cluster, and consistent with the results of IHC tests. Pathways like Notch and Wnt/β-catenin signaling transferred among above subgroups. Further, subgroups favored varied immune response and drug sensitivity, and CD133+ subgroup patients showed significantly shortened recurrence-free survival (RFS).ConclusionsConfiguring the subgroup of ICC is helpful for predicting the prognosis and drug resistance in ICC and can provide new strategies for cancer treatment.

Dataset Information

BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma.

Publications

BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma.

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