MALAT1: A Promising Therapeutic Target for the Treatment of Metastatic Colorectal Cancer

Uthman, Yaaqub Abiodun; Ibrahim, Kasimu Ghandi; Abubakar, Bilyaminu; Bello, Muhammad Bashir; Malami, Ibrahim; Imam, Mustapha Umar; Qusty, Naeem; Cruz‐Martins, Natália; Batiha, Gaber El‐Saber; Abubakar, Murtala Bello

doi:10.1016/j.bcp.2021.114657

Cited by 23 publications

(16 citation statements)

References 70 publications

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“…Our present study, as the largest sample size study to date, with external validation from an independent population, showed that MALAT1 expression was not associated with prognosis in CRC patients and that MALAT1 may have a potential tumor suppressive role in certain subpopulations. Most recently, MALAT1-based therapeutic approaches have gained increasing interest ( 38 , 39 ). Current researches involving MALAT1-targeted therapies are still in early stages and have not yet entered clinical testing ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA MALAT1 and Colorectal Cancer: A Propensity Score Analysis of Two Prospective Cohorts

Zhang

Liu

et al. 2022

Front. Oncol.

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BackgroundPrevious researches have shown that the aberrant expression of Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in tumour tissues may serve as a biomarker for colorectal cancer (CRC) prognosis. However, these previous studies have small sample sizes and lacked validation from independent external populations. We therefore aimed to clarify the prognostic value of MALAT1 expression status in CRC patients using a large cohort and validate the findings with another large external cohort.MethodsThe prognostic association between MALAT1 expression status and CRC outcomes was evaluated initially in a prospective cohort in China (n=164) and then validated in an external TCGA population (n=596). In the initial cohort, MALAT1 expression levels were quantified by quantitative reverse transcriptase polymerase chain reaction. Propensity score (PS) adjustment method was used to control potential confounding biases. The prognostic significance was reported as PS-adjusted hazard ratio (HR) and corresponding 95% confidence interval (CI).ResultsThere was no statistically significant association between MALAT1 expression status and CRC patient overall survival (OS) or disease free survival (DFS) in both initial cohort and external validation cohort populations. When combining these populations together, the results did not change materially. The summarized HRPS-adjusted were 1.010 (95% CI, 0.752-1.355, P=0.950) and 1.170 (95% CI, 0.910-1.502, P=0.220) for OS and DFS, respectively.ConclusionsMALAT1 expression status is not associated with prognostic outcomes of CRC patients. However, additional larger population studies are needed to further validate these findings.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA MALAT1 and Colorectal Cancer: A Propensity Score Analysis of Two Prospective Cohorts

Zhang

Liu

et al. 2022

Front. Oncol.

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“…A precursor transcript of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), also known as Nuclear-Enriched Abundant Transcript 2 (NEAT2), is almost 8.8 kb long, from which is derived an over eight kb lncRNA, which is localized in the nucleus (in nuclear specles) and involved in epigenetic modulation of gene expression and alternative splicing (Xu et al 2022 ; Uthman et al 2021 ). MALAT1 forms a fairly complex secondary structure with exposure of multiple miRNA-binding sites (McCown et al 2019 ).…”

Section: Malat1 and Other Lncrnas Affecting The Level Of Ty...mentioning

confidence: 99%

“…MALAT1 is overexpressed in many types of cancer (Goyal et al 2021 ), including CRCs (Younis et al 2022 ; Uthman et al 2021 ; Hu et al 2021 ; Zheng et al 2020 ; Xiong et al 2018 ; Yang et al 2015 ), metastatic lung cancers (Shen et al 2015 ), advanced stages of pancreatic cancers (Pang et al 2015 ). In general, high levels of MALAT1 expression have been demonstrated in the vast majority of CRC specimens compared to adjacent non-tumor control colorectal tissue specimens in cancer patients (Sun et al 2019b ; Zheng et al 2020 ; Luan et al 2020 ; Xiong et al 2018 ; Li et al 2017a ).…”

Section: Malat1 and Other Lncrnas Affecting The Level Of Ty...mentioning

confidence: 99%

MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy

Matuszyk

2022

Mol Med

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Background The active metabolite of 5-Fluorouracil (5FU), used in the treatment of several types of cancer, acts by inhibiting the thymidylate synthase encoded by the TYMS gene, which catalyzes the rate-limiting step in DNA replication. The major failure of 5FU-based cancer therapy is the development of drug resistance. High levels of TYMS-encoded protein in cancerous tissues are predictive of poor response to 5FU treatment. Expression of TYMS is regulated by various mechanisms, including involving non-coding RNAs, both miRNAs and long non-coding RNAs (lncRNAs). Aim To delineate the miRNAs and lncRNAs network regulating the level of TYMS-encoded protein. Main body Several miRNAs targeting TYMS mRNA have been identified in colon cancers, the levels of which can be regulated to varying degrees by lncRNAs. Due to their regulation by the MALAT1 lncRNA, these miRNAs can be divided into three groups: (1) miR-197-3p, miR-203a-3p, miR-375-3p which are downregulated by MALAT1 as confirmed experimentally and the levels of these miRNAs are actually reduced in colon and gastric cancers; (2) miR-140-3p, miR-330-3p that could potentially interact with MALAT1, but not yet supported by experimental results; (3) miR-192-5p, miR-215-5p whose seed sequences do not recognize complementary response elements within MALAT1. Considering the putative MALAT1-miRNAs interaction network, attention is drawn to the potential positive feedback loop causing increased expression of MALAT1 in colon cancer and hepatocellular carcinoma, where YAP1 acts as a transcriptional co-factor which, by binding to the TCF4 transcription factor/ β-catenin complex, may increase the activation of the MALAT1 gene whereas the MALAT1 lncRNA can inhibit miR-375-3p which in turn targets YAP1 mRNA. Conclusion The network of non-coding RNAs may reduce the sensitivity of cancer cells to 5FU treatment by upregulating the level of thymidylate synthase.

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“…Finally, another main field of research focuses on the role of a special category of lncRNAs, defined as intergenic, such as MALAT1, predominantly found in nuclear speckles, and which are associated with poor prognosis cancers. Its involvement in metastatic colorectal cancer was also recently reviewed (Uthman et al, 2021).…”

Section: Non-coding Rnasmentioning

confidence: 99%

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

et al. 2022

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Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

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MALAT1: A Promising Therapeutic Target for the Treatment of Metastatic Colorectal Cancer

Cited by 23 publications

References 70 publications

Long Noncoding RNA MALAT1 and Colorectal Cancer: A Propensity Score Analysis of Two Prospective Cohorts

Long Noncoding RNA MALAT1 and Colorectal Cancer: A Propensity Score Analysis of Two Prospective Cohorts

MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

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