CDX2 inducible microRNAs sustain colon cancer by targeting multiple DNA damage response pathway factors

Priya, Swati; Kaur, Ekjot; Kulshrestha, Swati; Pandit, Awadhesh; Groß, Isabelle; Kumar, Nitin; Agarwal, Himanshi; Khan, Aamir Ali; Shyam, Radhey; Bhagat, Prakash Kumar; Prabhu, Jyothi S; Nagarajan, Priyadharsini; Deo, S. V. S.; Bajaj, Avinash; Freund, Jean–Noël; Mukhopadhyay, Arnab; Sengupta, Sagar

doi:10.1242/jcs.258601

Cited by 5 publications

(3 citation statements)

References 82 publications

(89 reference statements)

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“…53 Another study showed that treatment with specific miR inhibitors in colon cancer reduced the high level of endogenous DNA damage sensitive miRs (DDSMs), increasing CHEK1 transcription level, which revealed the inhibitory effect of CHEK1 on colon cancer. 54 We found a novel miRNA signature risk score and analyzed its predictive effect on the prognosis of colon cancer. We have no conditions to collect our own clinical data to verify our model, which is a limitation of our study.…”

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confidence: 99%

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer

Yang¹,

Lü²,

Wang³

et al. 2022

IJGM

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This study aims at exploring the relationship between necroptosis-related miRNAs and colon cancer prognosis. Methods: We downloaded the miRNA sequencing data from the TCGA, and eight differentially expressed necroptosis-related miRNAs were screened. Then, we used Cox regression analysis to establish a prediction model of necroptosis-related miRNA. Finally, the prognosis related miRNAs were used to predict the target genes, and functional analysis was used to explore the potential mechanism of these target genes. Results:The miRNA-seq data of 444 COAD cases were downloaded from TCGA. We identified 8 differentially expressed miRNAs (has-miR-16-5p, has-miR-141-3p, has-miR -148a-3p, has-miR-425-5p, has-miR-7-5p, has-miR-223-3p, has-miR-200a-5p, and has-miR -500a-3p), then Cox analysis was performed for determining eight-miRNA signature prognostic biomarkers with obviously different OS. The area under the curve (AUC) of receiver operating characteristic (ROC) curve for predicting 1-, 3-, and 5-year survival were 0.663, 0.653 and 0.639, respectively. The multivariate analysis also implied that the risk score was an independent prognostic factor considering other confounding factors (HR = 1.847, 95% CI = 1.197-2.848, P = 0.006). According to the Kaplan-Meier analysis, the expression of hsa-miR-500a-3p (P = 0.003), hsa-miR-16-5p (P = 0.004) and hsa-miR-148a-3p (P = 0.035) significantly affected OS outcomes. We predicted the target genes of these three miRNAs and then screened 10 hub genes (CCND1, SMAD3, SMAD2, CDK1, TGFB2, CDC25A, CHEK1, VEGFA, CCNE1, WEE1). In addition, CHEK1 was associated with the survival prognosis. Conclusion: Our study demonstrated that necroptosis is closely associated with colon cancer, and the model of eight necroptosis-related miRNAs are potentially useful prognostic biomarkers and therapeutic targets for colon cancer.

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confidence: 99%

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer

Yang¹,

Lü²,

Wang³

et al. 2022

IJGM

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“…For experiments involving the shutdown of MRP2, BLM, or RAD54 in HCT116 WT IC60CPT R cells, cells were injected for tumor formation in mice. TAC6 polymermediated delivery of siControl, siMRP2, siBLM, and siRAD54 was carried out in the mice bearing 50 mm 3 tumors as described earlier (39). The delivery of the siRNAs (200 ng of siRNA per dose) was done every alternate day 4 times until the mice were sacrificed 21 days after initiation of the experiment.…”

Section: Discussionmentioning

confidence: 99%

Small molecules that disrupt RAD54-BLM interaction hamper tumor proliferation in colon cancer chemoresistance models

Kaur,

Agrawal,

Arun

et al. 2024

Journal of Clinical Investigation

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“…Group 2 and 3 mice were treated with 50 µL of 200 ng of siRNA complexed with TAC6 polymer (siRNA: TAC6 polymer; 1:10) at the tumor site. A total of 6 doses were given at an interval of every two day (63, 64). At the end of the experiment tumor was excised and stored at −80° C for further analysis.…”

Section: Methodsmentioning

confidence: 99%

RICTOR Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression

Rajput

Ansari

Jha³

et al. 2022

Preprint

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Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside synthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in Luminal breast cancer-specific MCF-7 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian Luminal breast cancer patient samples, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.

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CDX2 inducible microRNAs sustain colon cancer by targeting multiple DNA damage response pathway factors

Cited by 5 publications

References 82 publications

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer

Small molecules that disrupt RAD54-BLM interaction hamper tumor proliferation in colon cancer chemoresistance models

RICTOR Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression

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