Inhibition of MALAT1 reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer

Tang, Dongdong; Yang, Zhu; Long, Fengxi; Luo, Li; Yang, Bing; Zhu, Ruyi; Sang, Xianan; Cao, Gang

doi:10.1016/j.cellsig.2019.01.013

Cited by 46 publications

(42 citation statements)

References 38 publications

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“…In addition, competitive endogenous RNA (ceRNA) was reported that formed a large-scale regulatory network across the transcriptome. MALAT1 was overexpressed in six CRC cell lines and regulated the metastasis and invasion of CRC cells via targeting miR-20b-5p [21]. However, exosome-derived MALAT1 modulating CRC progression by interacting with miRNAs has not been addressed.…”

Section: Discussionmentioning

confidence: 99%

“…It plays essential roles in tumor development and is highly expressed in several tumors [20]. In CRC, inhibition of MALAT1 suppresses CRC progression and metastasis and improves the sensitivity of cancer cells to 5-FU [21]. Moreover, MALAT1 regulates the miR-106b-5p expression and further mediates the mobility of SLAIN2-related microtubules by functioning as a competing endogenous RNA, which results in the progression of CRC [22].…”

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confidence: 99%

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Exosomal MALAT1 sponges miR-26a/26b to promote the invasion and metastasis of colorectal cancer via FUT4 enhanced fucosylation and PI3K/Akt pathway

Xiao

Liu

et al. 2020

J Exp Clin Cancer Res

101

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Background: Exosomes are vesicles of endocytic origin released by various cell types and emerging as important mediators in tumor cells. Human metastases-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA known to promote cell proliferation, metastasis, and invasion in colorectal cancer (CRC).Methods: The expression of MALAT1 was analyzed in CRC using qRT-PCR. FUT4 and fucosylation levels were detected in CRC clinical samples and CRC cell lines by immunofluorescent staining, western blot and lectin blot analysis. CRC derived exosomes were isolated and used to examine their tumor-promoting effects in vitro and in vivo. Results:The invasive and metastatic abilities of primary CRC cells were enhanced after exposure to exosomes derived from highly metastatic CRC cells, which increased the fucosyltransferase 4 (FUT4) levels and fucosylation not by directly transmitting FUT4 mRNA. Exosomal MALAT1 increased FUT4 expresssion via sponging miR-26a/26b. Furthermore, MALAT1/miR-26a/26b/FUT4 axis played an important role in exosome-mediated CRC progression. Exosomal MALAT1 also mediated FUT4-associated fucosylation and activated the PI3K/AKT/mTOR pathway.Conclusions: These data indicated that exosomal MALAT1 promoted the malignant behavior of CRC cells by sponging miR-26a/26b via regulating FUT4 and activating PI3K/Akt/mTOR pathway.Keywords: CRC, Exosomal MALAT1, FUT4, miR-26a/26b, PI3K/Akt/mTOR pathway Background Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality [1,2]. More than 60% of CRC patients have initiated the metastatic process by the time of diagnosis [3]. Although there are multiple tests available for CRC screening, each method has its own limitations in terms of sensitivity and specificity. To the best of our knowledge, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are well established tumor markers with low sensitivity and specificity for early detection of CRC [4]. Hence, ideal CRC-specific biomarkers are urgently required to improve the current CRC diagnostic strategies.Exosomes, membrane vesicles of endocytic origin ranging in size from 30 to 150 nm approximately, are emerging as key players in intercellular communication between cancer cells and their microenvironment [5]. A distinct feature of exosomes is that they efficiently carry and deliver molecular signatures (proteins, lipids, RNA

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Exosomal MALAT1 sponges miR-26a/26b to promote the invasion and metastasis of colorectal cancer via FUT4 enhanced fucosylation and PI3K/Akt pathway

Xiao

Liu

et al. 2020

J Exp Clin Cancer Res

101

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“…82 It was reported that silencing MALAT-1 reduced the expression of drug resistance genes such as MDR1, MRP1, breast cancer resistance protein (BCRP), and ATP-binding cassette (ABC) transporters by upregulating miR-20b-5p, which induced apoptosis, inhibited EMT, and enhanced 5-FU sensitivity. 84 Interestingly, the stemness factor OCT4 is another downstream effector of miR-20b-5p; 85 the MALAT-1/miR-20b-5p/OCT4 axis was found to be involved in maintaining a stem cell-like phenotype and metabolic activity, which were correlated in tumorgenesis. 86 Thus, inhibiting the expression of MALAT-1 is a potential strategy for CRC treatment.…”

Section: Lung Carcinomamentioning

confidence: 99%

<p>Regulatory Networks of LncRNA MALAT-1 in Cancer</p>

Fu¹,

Wang²,

Li³

et al. 2020

CMAR

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Long noncoding (lnc)RNAs are a group of RNAs with a length greater than 200 nt that do not encode a protein but play an essential role in regulating the expression of target genes in normal biological contexts as well as pathologic processes including tumorigenesis. The lncRNA metastasis-associated lung adenocarcinoma transcript (MALAT)-1 has been widely studied in cancer. In this review, we describe the known functions of MALAT-1; its mechanisms of action; and associated signaling pathways and their clinical significance in different cancers. In most malignancies, including lung, colorectal, thyroid, and other cancers, MALAT-1 functions as an oncogene and is upregulated in tumors and tumor cell lines. MALAT-1 has a distinct mechanism of action in each cancer type and is thus at the center of large gene regulatory networks. Dysregulation of MALAT-1 affects cellular processes such as alternative splicing, epithelial-mesenchymal transition, apoptosis, and autophagy, which ultimately results in the abnormal cell proliferation, invasion, and migration that characterize cancers. In other malignancies, such as glioma and endometrial carcinoma, MALAT-1 functions as a tumor suppressor and thus forms additional regulatory networks. The current evidence indicates that MALAT-1 and its associated signaling pathways can serve as diagnostic or prognostic biomarker or therapeutic target in the treatment of many cancers.

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“…Based on the aforementioned findings, the present study further clarified a new direction for future investigations on ESCC development, which suggested that the interactions between the target mRNAs and miR-20b-5p could become the clues for novel ESCC diagnostic or treatment methods. 52 In summary, for the first time, this study reported valuable evidence that increased miR-20b-5p expressions induced by promoter hypomethylation could modulate ESCC growth and metastasis via targeting RB1 and TP53INP1. Moreover, it was suggested that serum Numbers may be less than the total number if missing data.…”

Section: Discussionmentioning

confidence: 69%

Functional Significance and Therapeutic Potential of miRNA-20b-5p in Esophageal Squamous Cell Carcinoma

Chen

Niu

et al. 2020

Molecular Therapy - Nucleic Acids

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Novel therapies tailored to the molecular composition mechanism of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. miR-20b-5p expression was significantly upregulated in cancerous tissues and associated with lymph node metastasis, clinical stage, and overall survival (OS). An analysis of the methylation status of the miR-20b-5p gene indicated that the hypomethylation of the CpG sites located upstream of the miR-20b-5p gene in the ESCC tissues was more frequent than in the adjacent normal tissues, and the methylation status of miR-20b-5p correlated inversely with its expression levels. Notably, a series of gain-and loss-of-function assays elucidated that miR-20b-5p promoted ESCC cell proliferation, migration, and invasion both in vitro and in vivo. Luciferase reporter assays, western blot, and qRT-PCR revealed that RB1 and TP53INP1 were the direct targets of miR-20b-5p. Moreover, the effects of ectopic miR-20b-5p expression were abrogated by RB1 and TP53INP1 overexpression. In contrast, the effects of miR-20b-5p depletion were impaired by RB1 and TP53INP1 knockdown. Treatment with a miR-20b-5p antagomir dramatically increased tumor growth and inhibited RB1 and TP53INP1 protein expression in nude mice. This work provided novel insights on the molecular mechanism of ESCC and further provided suggestions for therapy development.

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Inhibition of MALAT1 reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer

Cited by 46 publications

References 38 publications

Exosomal MALAT1 sponges miR-26a/26b to promote the invasion and metastasis of colorectal cancer via FUT4 enhanced fucosylation and PI3K/Akt pathway

Exosomal MALAT1 sponges miR-26a/26b to promote the invasion and metastasis of colorectal cancer via FUT4 enhanced fucosylation and PI3K/Akt pathway

<p>Regulatory Networks of LncRNA MALAT-1 in Cancer</p>

Functional Significance and Therapeutic Potential of miRNA-20b-5p in Esophageal Squamous Cell Carcinoma

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