Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

Mahdi, Mohamed R.; Georges, Rania; Ali, Doaa M.; Bedeer, Raouf Fekry; Eltahry, Huda; Gabr, Abdel; Berger, Martin R.

doi:10.3389/fphar.2020.00180

Cited by 6 publications

(7 citation statements)

References 57 publications

(76 reference statements)

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“…In addition, Fu et al (42) reported that miR-124-3p suppressed cell proliferation and invasion by the direct regulation of EDNRB in bladder cancer. By contrast, EDNRB expression has been shown to be downregulated by aberrant hypermethylation in the promoter site in several tumors, including hepatocellular carcinoma, gastric cancer and CRC (43)(44)(45). A reduced EDNRB expression by hypermethylation has been found to be associated with gastric cancer invasion and to be associated with pathological stage in prostate cancer (46).…”

Section: Discussionmentioning

confidence: 99%

The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation

et al. 2022

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Endothelin receptor A (EDNRA) has been reported to play various crucial physiological roles and has been shown to be associated with the pathology of several diseases, including colorectal cancer (CRC). However, the molecular mechanisms of EDNRA in the development of human CRC have not been fully elucidated to date. In this context, the present study was performed to investigate biological functions and novel downstream signaling pathways affected by EDNRA, during CRC progression. First, using public data repositories, it was observed that the EDRNA expression levels were markedly increased in CRC tissues, as compared to normal tissues. Patients with CRC with an increased EDNRA expression exhibited a significantly decreased survival rate in comparison with those with a lower EDNRA expression. Furthermore, a positive correlation between the levels of EDNRA and its ligand, EDN1, was found in CRC tissues. The ectopic expression of EDNRA or its ligand, EDN1, promoted, whereas the silencing of EDNRA or EDN1 decreased cell proliferation and migration in vitro. To elucidate the signaling pathways involved in the regulation of EDNRA expression in CRC cells, a phosphokinase array analysis was performed, and it was observed that the knockdown of EDNRA substantially suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in CRC cells. Of note, STAT3 silencing simultaneously decreased EDN1 and EDNRA expression, with the expression of EDN1 and/or EDNRA appearing to be directly regulated by binding STAT3 to their promoter region, according to chromatin immunoprecipitation and promoter assays, ultimately indicating a positive feedback loop in the expression of EDNRA and EDN1. It was also observed that treatment with an EDNRA antagonist (macitentan), alone or in combination with cisplatin, suppressed cell growth and migration ability, and induced cell apoptosis. Collectively, these data suggest a critical role of the EDN1/EDNRA signaling pathway in CRC progression. Thus, the pharmacological intervention of this signaling pathway may prove to be a potential therapeutic approach for patients with CRC.

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Section: Discussionmentioning

confidence: 99%

The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation

et al. 2022

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“…A new study points out the mechanism exerted by methylation on endothelin system genes expression can be compromised in CRLM. 317 Notably, CSCs are critical for the formation and maintenance of liver metastasis. Together, our data highlights distinct CSC dependencies for primary versus metastatic tumor growth and suggest that targeting CSCs may be one direction of treatment for CRLM.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Colorectal liver metastasis: molecular mechanism and interventional therapy

Zhou

Liu

Wang

et al. 2022

Sig Transduct Target Ther

139

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Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.

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“…When metastatic cell lines were exposed to Decitabine (DAC, which inhibits DNA methyltransferases), the expression of endothelin system genes did not increase, indicating that these gene expression changes were not caused by DNA methylation. This suggests that the regulatory function of epigenetic alterations may be gradually lost in the late stage of metastasis [ 67 ]. The microenvironment-induced epigenetic mutation is an essential mechanism for metastatic tumor cells to grow in their new niche.…”

Section: The Underlying Molecular Mechanisms and Contributing Factors...mentioning

confidence: 99%

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated

et al. 2022

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Metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the liver is the most common site of metastasis. Tumor cell metastasis can be thought of as an invasion-metastasis cascade and metastatic organotropism is thought to be a process that relies on the intrinsic properties of tumor cells and their interactions with molecules and cells in the microenvironment. Many studies have provided new insights into the molecular mechanism and contributing factors involved in CRC liver metastasis for a better understanding of the organ-specific metastasis process. The purpose of this review is to summarize the theories that explain CRC liver metastasis at multiple molecular dimensions (including genetic and non-genetic factors), as well as the main factors that cause CRC liver metastasis. Many findings suggest that metastasis may occur earlier than expected and with specific organ-anchoring property. The emergence of potential metastatic clones, the timing of dissemination, and the distinct routes of metastasis have been explained by genomic studies. The main force of CRC liver metastasis is also thought to be epigenetic alterations and dynamic phenotypic traits. Furthermore, we review key extrinsic factors that influence CRC cell metastasis and liver tropisms, such as pre-niches, tumor stromal cells, adhesion molecules, and immune/inflammatory responses in the tumor microenvironment. In addition, biomarkers associated with early diagnosis, prognosis, and recurrence of liver metastasis from CRC are summarized to enlighten potential clinical practice, including some markers that can be used as therapeutic targets to provide new perspectives for the treatment strategies of CRC liver metastasis.

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Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

Cited by 6 publications

References 57 publications

The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation

The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation

Colorectal liver metastasis: molecular mechanism and interventional therapy

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated

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