bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2022–02–13
seven papers selected by
Maria-Virginia Giolito, IRFAC/UMR-S1113 INSERM
  1. Thyroid hormone receptor α controls larval intestinal epithelial cell death by regulating the CDK1 pathway.
  2. Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion.
  3. Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts.
  4. Bcl-xL DNAzymes promote radiosensitivity and chemosensitivity in colorectal cancer cells via enhancing apoptosis.
  5. ST3GAL2 knock-down decreases tumoral character of colorectal cancer cells in vitro and in vivo.
  6. Sestrin2 reduces cancer stemness via Wnt/β-catenin signaling in colorectal cancer.
  7. Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling.
  1. Commun Biol. 2022 02 07. 5(1): 112
    Thyroid hormone receptor α controls larval intestinal epithelial cell death by regulating the CDK1 pathway.
    Yuta Tanizaki, Hongen Zhang, Yuki Shibata, Yun-Bo Shi.
      Thyroid hormone (T3) regulates adult intestine development through T3 receptors (TRs). It is difficult to study TR function during postembryonic intestinal maturation in mammals due to maternal influence. We chose intestinal remodeling during Xenopus tropicalis metamorphosis as a model to study TR function in adult organ development. By using ChIP (chromatin immunoprecipitation)-Seq, we identified over 3000 TR-bound genes in the intestine of premetamorphic wild type or TRα (the major TR expressed during premetamorphosis)-knockout tadpoles. Surprisingly, cell cycle-related GO (gene ontology) terms and biological pathways were highly enriched among TR target genes even though the first major event during intestinal metamorphosis is larval epithelial cell death, and TRα knockout drastically reduced this enrichment. More importantly, treatment of tadpoles with cell cycle inhibitors blocked T3-induced intestinal remodeling, especially larval epithelial cell death, suggesting that TRα-dependent activation of cell cycle is important for T3-induced apoptosis during intestinal remodeling.
    DOI:  https://doi.org/10.1038/s42003-022-03061-0
  2. Elife. 2022 Feb 08. pii: e73926. [Epub ahead of print]11
    Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion.
    Gerard Cantero-Recasens, Josune Alonso-Marañón, Teresa Lobo-Jarne, Marta Garrido, Mar Iglesias, Lluis Espinosa, Vivek Malhotra.
      15% of colorectal cancers (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that colorectal cancer cells build a barrier to chemotherapeutics by increasing mucins' secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al., 2018), is a risk factor for CRC patients' relapse in subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-Fluorouracil plus Irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3 overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. Similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous colorectal cancer cells and other mucinous tumours.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.73926
  3. Exp Biol Med (Maywood). 2022 Feb 08. 15353702221076793
    Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts.
    Fan Liu, Huan Yang, Xinyu Zhang, Xianglin Sun, Jiamin Zhou, Yuan Li, Yifei Liu, Zhixiang Zhuang, Guohua Wang.
      Musashi-1 (MSI1), a neural RNA-binding protein, is considered a gastric and intestinal stem cell marker. Although the function of MSI1 in gastric cancer has attracted increasing interest, it is not known whether MSI1 can be used as a biomarker to monitor gastric cancer development and response to treatment. Here, the role of MSI1 in the chemotherapeutic sensitivity of gastric cancer was investigated. Patients with high MSI1 levels had poor outcomes, implicating the gene in the development and progression of the disease. We overexpressed and silenced MSI1 in the human gastric cancer cell lines MKN45 and HGC27, finding that knockdown reduced proliferation, invasion, and migration, while promoting apoptosis. A patient-derived xenograft gastric cancer model was constructed in which mice received chemical drugs, si-MSI1, or a drug-si-MSI1 combination. It was found that blocking MSI1 expression reduced gastric cancer drug tolerance. The combination treatment with si-MSI1 was superior to 5F-dUMP and cisplatin, either separately or in combination, indicating that including si-MSI1 was better than drug therapy alone. Transcriptome sequencing analysis showed that MSI1 altered cell cycle regulation and growth signal transduction, including that of blood vessel epicardial substance (BVES). These results suggest that MSI1 reduces the tolerance of gastric cancer to chemical drugs through modulation of MSI1/BVES signaling.
    Keywords:  Musashi-1; RNA sequencing; chemotherapy sensitivity; gastric cancer; patient-derived xenograft
    DOI:  https://doi.org/10.1177/15353702221076793
  4. BMC Pharmacol Toxicol. 2022 02 05. 23(1): 13
    Bcl-xL DNAzymes promote radiosensitivity and chemosensitivity in colorectal cancer cells via enhancing apoptosis.
    Zhen Yu, Jun Guo, Tao Meng, Lei Ge, Lin Liu, Haijiang Wang, Xinhui Yang.
       BACKGROUND: RNA-cleaving deoxyribozymes (DNAzymes) are catalytic deoxyribonucleic acid molecules that have become a promising new class of gene suppressors by binding and cleaving target mRNA. This study investigated whether DNAzymes targeting Bcl-xL enhanced the effectiveness of radiotherapy and chemotherapy in colorectal cancer (CRC) cells.
    METHODS: Two types of CRC cells, SW480 and SW837, were transfected with five DNAzymes. Cell viability, Bcl-xL expression and apoptosis were examined. SW480 xenograft model was used to examine the combined effects of Bcl-xL DNAzymes and 5-FU (or X-rays) on tumor growth.
    RESULTS: Three Bcl-xL DNAzymes, DT882, DT883, and DT884 were identified to be effective in suppressing Bcl-xL expression and causing cell apoptosis. Furthermore, DT882 combined with 5-FU or radiotherapy addictively promoted cell apoptosis and significantly inhibited the growth of SW480 xenografts in vivo.
    CONCLUSIONS: These results suggest that Bcl-xL DNAzymes can enhance the radiosensitivity and chemosensitivity in CRC cells via inducing apoptosis.
    Keywords:  5-fluorouracil; Bcl-xL; Colorectal cancer cells; DNAzyme; Radiotherapy
    DOI:  https://doi.org/10.1186/s40360-022-00553-x
  5. Am J Cancer Res. 2022 ;12(1): 280-302
    ST3GAL2 knock-down decreases tumoral character of colorectal cancer cells in vitro and in vivo.
    Marlène Deschuyter, David Yannick Leger, Anne Verboom, Alain Chaunavel, Abderrahman Maftah, Jean-Michel Petit.
      Tumor cells have a modified glycosylation profile that promotes their evolution and/or their maintenance in the tumor. Sialylation is a type of glycosylation that is often altered in cancers. RNA-Seq database analysis revealed that the sialyltransferase gene ST3GAL2 is significantly overexpressed at all stages of colorectal cancer (CRC). ST3GAL2 sialylates both glycoproteins and glycolipids. The aim of this work was to investigate the involvement of ST3GAL2 in CRC. Using the HT29 tumor cell line derived from a stage II of CRC, we decreased the expression of ST3GAL2 by specific shRNA, and then characterized these cells by performing functional tests. We found that ST3GAL2 knock down (KD) significantly decreases tumor cell proliferation, cell migration and invasiveness properties in vitro. The cell cycle of these cells is affected with a change in cell cycle distribution and an increase of cell apoptosis. The effect of ST3GAL2 KD was then studied in vivo, following xenografts into nude mice, in which the tumor progression was significantly reduced. This work demonstrates that ST3GAL2 is a major player in the behavior of colorectal tumor cells, by modifying the sialylation state of glycoproteins and glycolipids which remain to be specifically identified.
    Keywords:  HT29; ST3GAL2; biopsies; colorectal cancer; xenografts
  6. Cancer Cell Int. 2022 Feb 11. 22(1): 75
    Sestrin2 reduces cancer stemness via Wnt/β-catenin signaling in colorectal cancer.
    Jinlai Wei, Xiangru Zheng, Wenjun Li, Xiaoli Li, Zhongxue Fu.
       BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in both men and women in China. In previous studies, Sestrin2 was demonstrated to have functions in CRC. However, the relationship between Sestrin2 and cancer stemness has not been reported.
    METHODS AND RESULTS: To investigate the contribution of Sestrin2 in CRC, we performed bioinformatics analysis of The Cancer Genome Atlas datasets and found that Sestrin2 was downregulated in CRC. Using a lentivirus vector, we verified that Sestrin2 suppressed CRC cell proliferation, migration, and colony formation. Furthermore, sphere formation, flow cytometry, quantitative PCR, and western blot analysis verified the influence of Sestrin2 on cancer stemness, including the expression of cluster of differentiation 44, octamer-binding transcription factor 4, sex-determining region Y-Box 2, CXC chemokine receptor 4, and the Wnt pathway downstream factors β-catenin and c-Myc. Consistently, the Wnt pathway activator BML-284 partially rescued the effects of Sestrin2 on the expression of proteins related to cancer stemness. Furthermore, in a mouse xenoplant model, tumors expressing Sestrin2 were significantly reduced in size with corresponding changes in cancer stemness.
    CONCLUSIONS: Collectively, our results suggest that Sestrin2 inhibits CRC cell progression by downregulating the Wnt signaling pathway. Thus, Sestrin2 may be a promising therapeutic target for CRC.
    Keywords:  Cancer stemness; Colorectal cancer; Sestrin2; Therapeutic target; Wnt/β-catenin
    DOI:  https://doi.org/10.1186/s12935-022-02498-x
  7. Nat Commun. 2022 Feb 07. 13(1): 715
    Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling.
    Martti Maimets, Marianne Terndrup Pedersen, Jordi Guiu, Jes Dreier, Malte Thodberg, Yasuko Antoku, Pawel J Schweiger, Leonor Rib, Raul Bardini Bressan, Yi Miao, K Christopher Garcia, Albin Sandelin, Palle Serup, Kim B Jensen.
      Organs are anatomically compartmentalised to cater for specialised functions. In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. While several studies indicate the critical importance of non-epithelial cells during development and homeostasis, the extent to which these cells contribute to regionalisation during morphogenesis remains unexplored. Here, we identify a mesenchymal-epithelial crosstalk that shapes the developing SI during late morphogenesis. We find that subepithelial mesenchymal cells are characterised by gradients of factors supporting Wnt signalling and stimulate epithelial growth in vitro. Such a gradient impacts epithelial gene expression and regional villus formation along the anterior-posterior axis of the SI. Notably, we further provide evidence that Wnt signalling directly regulates epithelial expression of Sonic Hedgehog (SHH), which, in turn, acts on mesenchymal cells to drive villi formation. Taken together our results uncover a mechanistic link between Wnt and Hedgehog signalling across different cellular compartments that is central for anterior-posterior regionalisation and correct formation of the SI.
    DOI:  https://doi.org/10.1038/s41467-022-28369-7
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