bims-instec 2024-08-04 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2024‒08‒04
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Targeting epigenetic alterations in cancer stem cells.
Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome.
ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells.
HOXC11-mediated regulation of mitochondrial function modulates chemoresistance in colorectal cancer.
Establishment of a 3D organoid culture model for the investigation of adult slow-cycling putative intestinal stem cells.
A second wave of Notch signaling diversifies the intestinal secretory lineage.
mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer.
Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.
Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway.
Peroxisomal cholesterol metabolism regulates yap-signaling, which maintains intestinal epithelial barrier function and is altered in Crohn's disease.
Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer.
Protocol for the application of single-cell damage in murine intestinal organoid models.
Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis.
Aldehyde dehydrogenase 2 family member repression promotes colorectal cancer progression by JNK/p38 MAPK pathways-mediated apoptosis and DNA damage.

Front Mol Med. 2022 ;2 1011882

Targeting epigenetic alterations in cancer stem cells.

Verona F, Pantina V D, Modica C, Lo Iacono M, D'Accardo C, Porcelli G, Cricchio D, Turdo A, Gaggianesi M, Di Franco S, Todaro M, Veschi V, Stassi G.

  Oncogenes or tumor suppressor genes are rarely mutated in several pediatric tumors and some early stage adult cancers. This suggests that an aberrant epigenetic reprogramming may crucially affect the tumorigenesis of these tumors. Compelling evidence support the hypothesis that cancer stem cells (CSCs), a cell subpopulation within the tumor bulk characterized by self-renewal capacity, metastatic potential and chemo-resistance, may derive from normal stem cells (NSCs) upon an epigenetic deregulation. Thus, a better understanding of the specific epigenetic alterations driving the transformation from NSCs into CSCs may help to identify efficacious treatments to target this aggressive subpopulation. Moreover, deepening the knowledge about these alterations may represent the framework to design novel therapeutic approaches also in the field of regenerative medicine in which bioengineering of NSCs has been evaluated. Here, we provide a broad overview about: 1) the role of aberrant epigenetic modifications contributing to CSC initiation, formation and maintenance, 2) the epigenetic inhibitors in clinical trial able to specifically target the CSC subpopulation, and 3) epigenetic drugs and stem cells used in regenerative medicine for cancer and diseases.

Keywords:  cancer stem cells; epigenetic alterations; epigenetic inhibitors; normal stem cells; regenerative medicine

DOI:  https://doi.org/10.3389/fmmed.2022.1011882
FASEB J. 2024 Aug 15. 38(15): e23847

Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome.

Yuling Zhao, Ying Wang, Lu Jiang, Wei Cai, Junkai Yan.

  Intestinal failure-associated liver disease (IFALD) is a serious complication of long-term parenteral nutrition in patients with short bowel syndrome (SBS), and is the main cause of death in SBS patients. Prevention of IFALD is one of the major challenges in the treatment of SBS. Impairment of intestinal barrier function is a key factor in triggering IFALD, therefore promoting intestinal repair is particularly important. Intestinal repair mainly relies on the function of intestinal stem cells (ISC), which require robust mitochondrial fatty acid oxidation (FAO) for self-renewal. Herein, we report that aberrant LGR5+ ISC function in IFALD may be attributed to impaired farnesoid X receptor (FXR) signaling, a transcriptional factor activated by steroids and bile acids. In both surgical biopsies and patient-derived organoids (PDOs), SBS patients with IFALD represented lower population of LGR5+ cells and decreased FXR expression. Moreover, treatment with T-βMCA in PDOs (an antagonist for FXR) dose-dependently reduced the population of LGR5+ cells and the proliferation rate of enterocytes, concomitant with decreased key genes involved in FAO including CPT1a. Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients.

Keywords:  carnitine palmitoyltransferase 1a; farnesoid X receptor; fatty acid oxidation; intestinal repair; intestinal stem cells; patient‐derived organoids; short bowel syndrome

DOI:  https://doi.org/10.1096/fj.202400827R
Cell Commun Signal. 2024 Aug 02. 22(1): 388

ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells.

Xing Wan, Feng Li, Zhigui Li, Liming Zhou.

  Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target.

Keywords:   De novo lipid synthesis; ASIC3; Acidic tumor microenvironment; Colorectal cancer; EMT; Metastasis

DOI:  https://doi.org/10.1186/s12964-024-01762-z
BMC Cancer. 2024 Jul 30. 24(1): 921

HOXC11-mediated regulation of mitochondrial function modulates chemoresistance in colorectal cancer.

Shicheng Chu, Xiang Ren, Lianmeng Cao, Chong Ma, Kai Wang.

  BACKGROUND: Chemoresistance remains a significant challenge in colorectal cancer (CRC) treatment, necessitating a deeper understanding of its underlying mechanisms. HOXC11 has emerged as a potential regulator in various cancers, but its role in CRC chemoresistance remains unclear.METHODS: Sulforhodamine B assay was employed to assess the cell viability of CRC cells following treatment with chemotherapeutic drugs. Immunofluorescence staining was performed to examine the subcellular localization of HOXC11 in normal and chemoresistant CRC cells. The Seahorse mito stress test was conducted to evaluate the mitochondrial respiratory function of CRC cells. Real-time PCR was utilized to measure the expression level and copy number of mitochondrial DNA (mtDNA).
RESULTS: Our findings revealed that HOXC11 was overexpressed in CRC cells compared to normal colorectal cells and correlated with poorer prognosis in CRC patients. Knockout of HOXC11 reversed acquired chemoresistance in CRC cells. Furthermore, we observed a functional subset of HOXC11 localized to the mitochondria in chemoresistant CRC cells, which regulated mitochondrial function by modulating mtDNA transcription, thereby affecting chemoresistance.
CONCLUSIONS: In summary, our study reveals that HOXC11 regulates mitochondrial function through the modulation of mtDNA transcription, impacting chemoresistance in colorectal cancer cells. These findings underscore the significance of understanding the molecular mechanisms underlying chemoresistance and highlight the potential therapeutic implications of targeting mitochondrial function in CRC treatment.

Keywords:  Chemoresistance; Chemotherapy; Colorectal cancer; Mitochondrial DNA; Mitochondrial respiration

DOI:  https://doi.org/10.1186/s12885-024-12698-5
Histochem Cell Biol. 2024 Jul 29.

Establishment of a 3D organoid culture model for the investigation of adult slow-cycling putative intestinal stem cells.

Maria Eugenia Gulino, Paloma Ordóñez-Morán, Yashwant R Mahida.

  The study of intestinal stem cells is a prerequisite for the development of therapies aimed at regenerating the gut. To enable investigation of adult slow-cycling H2B-GFP-retaining putative small intestinal (SI) stem cells in vitro, we have developed a three-dimensional (3D) SI organoid culture model based on the Tet-Op histone 2 B (H2B)-green fluorescent protein (GFP) fusion protein (Tet-Op-H2B-GFP) transgenic mouse. SI crypts were isolated from 6- to 12-week-old Tet-Op-H2B-GFP transgenic mice and cultured with appropriate growth factors and an animal-derived matrix (Matrigel). For in vitro transgene expression, doxycycline was added to the culture medium for 24 h. By pulse-chase experiments, H2B-GFP expression and retention were assessed through direct GFP fluorescence observations, both by confocal and fluorescence microscopy and by immunohistochemistry. The percentages of H2B-GFP-retaining putative SI stem cells and H2B-GFP-retaining Paneth cells persisting in organoids were determined by scoring relevant GFP-positive cells. Our results indicate that 24 h exposure to doxycycline (pulse) induced ubiquitous expression of H2B-GFP in the SI organoids. During subsequent culture, in the absence of doxycycline (chase), there was a gradual loss (due to cell division) of H2B-GFP. At 6-day chase, slow-cycling H2B-GFP-retaining putative SI stem cells and H2B-GFP-retaining Paneth cells were detected in the SI organoids. The developed culture model allows detection of slow-cycling H2B-GFP-retaining putative SI stem cells and will enable the study of self-renewal and regeneration for further characterization of these cells.

Keywords:  3 dimensions; Intestine; Organoids; Paneth cells; Regeneration; Stem cells

DOI:  https://doi.org/10.1007/s00418-024-02312-x
bioRxiv. 2024 Jul 16. pii: 2024.07.15.603542. [Epub ahead of print]

A second wave of Notch signaling diversifies the intestinal secretory lineage.

Eleanor Zagoren, Nicolas Dias, Zachary D Smith, Nadia A Ameen, Kaelyn Sumigray.

The small intestine is well known for the function of its nutrient-absorbing enterocytes; yet equally critical for the maintenance of homeostasis is a diverse set of secretory cells, all of which are presumed to differentiate from the same intestinal stem cell. Despite major roles in intestinal function and health, understanding how the full spectrum of secretory cell types arises remains a longstanding challenge, largely due to their comparative rarity. Here, we investigate the fate specification of a rare and distinct population of small intestinal epithelial cells found in rats and humans but not mice: C FTR Hi gh E xpressers (CHEs). We use pseudotime trajectory analysis of single-cell RNA-seq data from rat intestinal jejunum to provide evidence that CHEs are specified along the secretory lineage and appear to employ a second wave of Notch-based signal transduction to distinguish these cells from other secretory cell types. We further validate the general order of transcription factors that direct these cells from unspecified progenitors within the crypt and experimentally demonstrate that Notch signaling is necessary to induce CHE fate both in vivo and in vitro . Our results suggest a model in which Notch is reactivated along the secretory lineage to specify the CHE population: a rare secretory cell type with putative functions in localized coordination of luminal pH and direct relevance to cystic fibrosis pathophysiology.

DOI: https://doi.org/10.1101/2024.07.15.603542
Nat Cell Biol. 2024 Jul 30.

mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer.

Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2-ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells.

DOI: https://doi.org/10.1038/s41556-024-01473-0
World J Gastrointest Oncol. 2024 Jul 15. 16(7): 3032-3054

Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity.

Han-Xuan Liu, Jie Feng, Jing-Jing Jiang, Wan-Jun Shen, Yu Zheng, Gang Liu, Xiang-Yang Gao.

  BACKGROUND: Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development.AIM: To construct a robust prognostic signature, we used developed and validated across datasets.
METHODS: After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted.
RESULTS: In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples.
CONCLUSION: The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.

Keywords:  Colorectal cancer; Epigenetic regulation; Gene expression signature; Micro-environment; Prognosis

DOI:  https://doi.org/10.4251/wjgo.v16.i7.3032
Int Immunopharmacol. 2024 Aug 01. pii: S1567-5769(24)01349-3. [Epub ahead of print]140 112828

Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway.

Shixiong Liu, Yun Zhou, Yarong Chen, Yuqin Qiao, Lumucao Bai, Shenhua Zhang, Dongfang Men, Haibu Zhang, Fen Pan, Yongshen Gao, Jijing Wang, Yuping Wang.

  Changes in isocitrate dehydrogenases (IDH) lead to the production of the cancer-causing metabolite 2-hydroxyglutarate, making them a cause of cancer. However, the specific role of IDH in the progression of colon cancer is still not well understood. Our current study provides evidence that IDH2 is significantly increased in colorectal cancer (CRC) cells and actively promotes cell growth in vitro and the development of tumors in vivo. Inhibiting the activity of IDH2, either through genetic silencing or pharmacological inhibition, results in a significant increase in α-ketoglutarate (α-KG), indicating a decrease in the reductive citric acid cycle. The excessive accumulation of α-KG caused by the inactivation of IDH2 obstructs the generation of ATP in mitochondria and promotes the downregulation of HIF-1A, eventually inhibiting glycolysis. This dual metabolic impact results in a reduction in ATP levels and the suppression of tumor growth. Our study reveals a metabolic trait of colorectal cancer cells, which involves the active utilization of glutamine through reductive citric acid cycle metabolism. The data suggests that IDH2 plays a crucial role in this metabolic process and has the potential to be a valuable target for the advancement of treatments for colorectal cancer.

Keywords:  Citric acid cycle; Colorectal cancer; Glycolysis; Isocitrate dehydrogenases; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.intimp.2024.112828
Cell Death Dis. 2024 Jul 28. 15(7): 536

Peroxisomal cholesterol metabolism regulates yap-signaling, which maintains intestinal epithelial barrier function and is altered in Crohn's disease.

Marinella Pinelli, Stephanie Makdissi, Michal Scur, Brendon D Parsons, Kristi Baker, Anthony Otley, Brad MacIntyre, Huong D Nguyen, Peter K Kim, Andrew W Stadnyk, Francesca Di Cara.

Intestinal epithelial cells line the luminal surface to establish the intestinal barrier, where the cells play essential roles in the digestion of food, absorption of nutrients and water, protection from microbial infections, and maintaining symbiotic interactions with the commensal microbial populations. Maintaining and coordinating all these functions requires tight regulatory signaling, which is essential for intestinal homeostasis and organismal health. Dysfunction of intestinal epithelial cells, indeed, is linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, and gluten-related enteropathies. Emerging evidence suggests that peroxisome metabolic functions are crucial in maintaining intestinal epithelial cell functions and intestinal epithelium regeneration and, therefore, homeostasis. Here, we investigated the molecular mechanisms by which peroxisome metabolism impacts enteric health using the fruit fly Drosophila melanogaster and murine model organisms and clinical samples. We show that peroxisomes control cellular cholesterol, which in turn regulates the conserved yes-associated protein-signaling and contributes to intestinal epithelial structure and epithelial barrier function. Moreover, analysis of intestinal organoid cultures derived from biopsies of patients affected by Crohn's Disease revealed that the dysregulation of peroxisome number, excessive cellular cholesterol, and inhibition of Yap-signaling are markers of disease and could be novel diagnostic and/or therapeutic targets for treating Crohn's Disease. Our studies provided mechanistic insights on peroxisomal signaling in intestinal epithelial cell functions and identified cholesterol as a novel metabolic regulator of yes-associated protein-signaling in tissue homeostasis.

DOI: https://doi.org/10.1038/s41419-024-06925-x
Redox Biol. 2024 Jul 26. pii: S2213-2317(24)00264-7. [Epub ahead of print]75 103286

Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer.

Zhang Lin, Shiyi Yang, Qianqian Qiu, Gaoping Cui, Yanhua Zhang, Meilian Yao, Xiangyu Li, Chengkun Chen, Jun Gu, Ting Wang, Peng Yin, Longci Sun, Yujun Hao.

  Metabolic reprogramming is a hallmark of human cancer, and cancer-specific metabolism provides opportunities for cancer diagnosis, prognosis, and treatment. However, the underlying mechanisms by which metabolic pathways affect the initiation and progression of colorectal cancer (CRC) remain largely unknown. Here, we demonstrate that cysteine is highly enriched in colorectal tumors compared to adjacent non-tumor tissues, thereby promoting tumorigenesis of CRC. Synchronously importing both cysteine and cystine in colorectal cancer cells is necessary to maintain intracellular cysteine levels. Hypoxia-induced reactive oxygen species (ROS) and ER stress regulate the co-upregulation of genes encoding cystine transporters (SLC7A11, SLC3A2) and genes encoding cysteine transporters (SLC1A4, SLC1A5) through the transcription factor ATF4. Furthermore, the metabolic flux from cysteine to reduced glutathione (GSH), which is critical to support CRC growth, is increased due to overexpression of glutathione synthetase GSS in CRC. Depletion of cystine/cysteine by recombinant cyst(e)inase effectively inhibits the growth of colorectal tumors by inducing autophagy in colorectal cancer cells through mTOR-ULK signaling axis. This study demonstrates the underlying mechanisms of cysteine metabolism in tumorigenesis of CRC, and evaluates the potential of cysteine metabolism as a biomarker or a therapeutic target for CRC.

Keywords:  ATF4; Colorectal cancer; Cysteine/cystine; Hypoxia; ROS homeostasis; Transporter genes

DOI:  https://doi.org/10.1016/j.redox.2024.103286
STAR Protoc. 2024 Jul 30. pii: S2666-1667(24)00318-6. [Epub ahead of print]5(3): 103153

Protocol for the application of single-cell damage in murine intestinal organoid models.

Anna Elisabeth Seidler, Sören Donath, Lara Gentemann, Manuela Buettner, Alexander Heisterkamp, Stefan Kalies.

  Spatially defined organoid damage enables the study of cellular repair processes. However, capturing dynamic events in living tissues is technically challenging. Here, we present a protocol for the application of single-cell damage in intestinal organoid models. We describe steps for isolating and cultivating murine colon organoids, lentivirus generation and transduction of organoids, single-cell ablation by a femtosecond laser, and follow-up imaging analysis. We provide examples for the image acquisition pipeline of dynamic processes in organoids using a confocal microscope. For complete details on the use and execution of this protocol, please refer to Donath et al.1,2.

Keywords:  Biophysics; Microscopy; Molecular Biology; Organoids; Single Cell

DOI:  https://doi.org/10.1016/j.xpro.2024.103153
EMBO J. 2024 Jul 31.

Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis.

Caroline Wathieu, Arnaud Lavergne, Xinyi Xu, Marion Rolot, Ivan Nemazanyy, Kateryna Shostak, Najla El Hachem, Chloé Maurizy, Charlotte Leemans, Pierre Close, Laurent Nguyen, Christophe Desmet, Sylvia Tielens, Benjamin G Dewals, Alain Chariot.

  Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.

Keywords:  ATF4; Tuft Cells; mTORC1; tRNA Modifications

DOI:  https://doi.org/10.1038/s44318-024-00184-4
World J Gastrointest Oncol. 2024 Jul 15. 16(7): 3230-3240

Aldehyde dehydrogenase 2 family member repression promotes colorectal cancer progression by JNK/p38 MAPK pathways-mediated apoptosis and DNA damage.

Miao Yu, Qian Chen, Yi-Ping Lu.

  BACKGROUND: Aldehyde (ALDH2) dysfunction has been verified to contribute to human cancers.AIM: To investigate the molecular mechanism and biological function of ALDH2 in colorectal cancer (CRC) progression.
METHODS: Human CRC cells with high expression of ALDH2 were screened. After shRNA ALDH2 (sh-ALDH2) transfection, phenotypes [proliferation, apoptosis, acetaldehyde (ACE) accumulation, DNA damage] of CRC cells were verified using cell counting kit-8, flow cytometry, ACE assay, and comet assays. Western blotting was used for evaluation of the apoptosis proteins (Bax and Bcl-2) and JNK/p38 MAPK pathway-associated proteins. We subjected CVT-10216 (a selective ALDH2 inhibitor) to nude mice for establishment of SK-CO-1 mouse xenograft model and observed the occurrence of CRC.
RESULTS: The inhibition of ALDH2 could promote the malignant structures of CRC cells, including apoptosis, ACE level, and DNA damage, and cell proliferation was decreased in the sh-ALDH2 group, whereas ALDH2 agonist Alda-1 reversed features. ALDH2 repression can cause ACE accumulation, whereas ACE enhanced CRC cell features related to increased DNA damage. Additionally, ALDH2 repression led to JNK/P38 MAPK activation, and apoptosis, ACE accumulation, and DNA damage were inhibited after p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125 addition. ACE accumulation and raised DNA damage were recognized in CVT-10216 treated-mouse tumor tissues in vivo.
CONCLUSION: The repression of ALDH2 led to ACE accumulation, inducing cell apoptosis and DNA damage by the JNK/p38 MAPK signaling pathway activation in CRC.

Keywords:  Acetaldehyde; Aldehyde dehydrogenase 2 family member; Apoptosis; Colorectal cancer; DNA damage; JNK/p38 MAPK

DOI:  https://doi.org/10.4251/wjgo.v16.i7.3230