Enteric Glia Play a Critical Role in Promoting the Development of Colorectal Cancer

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

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Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

International Journal of Molecular Sciences ◽

10.3390/ijms22158117 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8117

Author(s):

Nunzia D’Onofrio ◽

Elisa Martino ◽

Luigi Mele ◽

Antonino Colloca ◽

Martina Maione ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Current Knowledge ◽

Apoptotic Cell ◽

Critical Role ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

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MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer

Cell Death and Differentiation ◽

10.1038/s41418-021-00820-0 ◽

2021 ◽

Author(s):

Andrea Lampis ◽

Jens C. Hahne ◽

Pierluigi Gasparini ◽

Luciano Cascione ◽

Somaieh Hedayat ◽

...

Keyword(s):

Colorectal Cancer ◽

Critical Role ◽

Tumour Volume ◽

Cell Permeability ◽

Oncogenic Pathways ◽

Morphogenetic Protein ◽

Cancer Phenotype ◽

And Migration ◽

2D And 3D

AbstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.

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Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

Cell Communication and Signaling ◽

10.1186/s12964-021-00712-3 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Camille Ternet ◽

Christina Kiel

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Intestinal Microbiota ◽

Critical Role ◽

Neuroendocrine Cells ◽

Cell Junction ◽

Intestinal Cell ◽

Intestinal Homeostasis ◽

Cell Functions ◽

The Impact

AbstractThe intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.

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Urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of colitis-associated colorectal cancer in mice

PLoS ONE ◽

10.1371/journal.pone.0245292 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245292

Author(s):

Yusuke Miyazaki ◽

Tatsuro Nakamura ◽

Shinya Takenouchi ◽

Akane Hayashi ◽

Keisuke Omori ◽

...

Keyword(s):

Colorectal Cancer ◽

Mass Spectrometry ◽

Liquid Chromatography ◽

Morphological Study ◽

Critical Role ◽

Repeated Administration ◽

Tumor Formation ◽

Liquid Chromatography Mass Spectrometry ◽

Chromatography Mass Spectrometry ◽

Lipid Metabolites

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E2 metabolite tetranor-PGEM and PGD2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F2 isoprostanes (F2-IsoPs), 8-iso PGF2α and 2,3-dinor-8-iso PGF2α, were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22phox). These observations suggest that urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of CAC.

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Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion

International Journal of Cancer ◽

10.1002/ijc.24987 ◽

2010 ◽

pp. NA-NA ◽

Cited By ~ 2

Author(s):

Hiroyuki Hayashi ◽

Kazuki Nabeshima ◽

Mikiko Aoki ◽

Makoto Hamasaki ◽

Sotaro Enatsu ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Invasion ◽

Poor Prognosis ◽

Advanced Colorectal Cancer ◽

Critical Role

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MiR-382 functions as tumor suppressor and chemosensitizer in colorectal cancer

Bioscience Reports ◽

10.1042/bsr20180441 ◽

2019 ◽

Vol 39 (8) ◽

Cited By ~ 12

Author(s):

Hui Yao ◽

Dong Xia ◽

Zong-lin Li ◽

Lei Ren ◽

Ming-ming Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Suppressor ◽

Cell Lines ◽

Cancer Cell ◽

Critical Role ◽

Colorectal Cancer Cell ◽

Cancer Cell Proliferation ◽

Interacting Protein ◽

Colorectal Cancer Cell Lines ◽

Cancer Tissues

Abstract Increasing evidence suggests that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miR-382 has been observed in various types of cancers. However, the biological function of miR-382 in colorectal cancer (CRC) is still largely unknown. Here, we found that miR-382 was down-regulated in human colorectal cancer tissues and cell lines associated with it. MiR-382 inhibited colorectal cancer cell proliferation, migration, invasion, and enhance chemosensitivity. Furthermore, we identified Krüppel-like factor 12 (KLF12) and homeodomain-interacting protein kinase 3 (HIPK3) as the target of miR-382, and miR-382 rescued the promotion effect of KFL12 on migration and enhanced chemosensitivity in colorectal cancer cell lines. Collectively, these findings revealed that miR-382 inhibits migration and enhances chemosensitivity by targeting KLF12 and HIPK3 in colorectal cancer. These findings might serve as a tumor suppressor in CRC.

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Abstract 1558: The critical role of lymph node stromal cell-derived microvesicles in colorectal cancer metastasis

10.1158/1538-7445.am2016-1558 ◽

2016 ◽

Author(s):

Xin Zhang ◽

Ryan Sullivan ◽

Nathan Hite ◽

Grace Maresh ◽

Linh Hellmers ◽

...

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Stromal Cell ◽

Cancer Metastasis ◽

Critical Role ◽

Colorectal Cancer Metastasis

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KIF20A Predicts Poor Survival of Patients and Promotes Colorectal Cancer Tumor Progression through the JAK/STAT3 Signaling Pathway

Disease Markers ◽

10.1155/2020/2032679 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Qi Zhang ◽

Jun Di ◽

Zhiyu Ji ◽

Aoning Mi ◽

Quanying Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Progression ◽

Cox Regression ◽

Critical Role ◽

Depth Of Invasion ◽

Cox Regression Analysis ◽

Normal Tissues ◽

Reduce Cell Proliferation ◽

Cancer Tumor ◽

And Migration

Kinesin family member 20A (KIF20A) has been recently reported to be upregulated and associated with increased invasiveness and metastasis in several malignancies. However, the role of KIF20A in colorectal cancer (CRC) is still unclear. This study is aimed at investigating the potential roles of KIF20A in the development of CRC. The results of bioinformatics analysis, immunohistochemical staining, and Western blot analysis showed that KIF20A was overexpressed in CRC tissues compared with adjacent normal tissues. High expression of KIF20A in CRC tissues was associated with depth of invasion, lymphatic node metastasis, distant metastasis, and TNM stage. Moreover, the Kaplan-Meier survival analysis showed that CRC patients with high KIF20A expression had poor prognoses. Cox regression analysis revealed that KIF20A was an independent prognostic factor in patients with CRC. Further studies suggested that knockdown of KIF20A was able to reduce cell proliferation and migration by inhibiting the JAK/STAT3 pathway. Taken together, we propose that KIF20A plays a critical role in the tumorigenesis and tumor progression of colorectal cancer and could represent a potential therapeutic target for CRC.

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