Abstract
MicroRNA-34a (miR-34a) is down-regulated in colorectal cancers (CRC) and required for interleukin-6 (IL-6)-induced CRC metastasis. Mice lacking miR-34a developed more invasive cancer in a colitis-associated cancer model. In the same model, S-adenosylmethionine (SAMe) and methylthioadenosine (MTA) inhibited IL-6/STAT3 and lowered tumor burden. SAMe and MTA reduce the expression of methionine adenosyltransferase 2A (MAT2A) and there are consensus binding sites for miR-34a/b in the MAT2A 3’UTR. Here we examined whether SAMe/MTA influence miR-34a/b expression and cancer metastasis. We found SAMe and MTA raised miR-34a/b expression in CRC cell lines, inhibited migration and invasion in vitro and liver metastasis in vivo. Like CRC, MAT2A and MAT2B expression is induced in human pancreas and prostate cancers. Treatment with SAMe, MTA, miR-34a or miR-34b inhibited MAT2A expression mainly at the protein level. MAT2B protein level also fell because MAT2A and MAT2B enhance each other’s protein stability. Overexpressing miR-34a or miR-34b inhibited while MAT2A or MAT2B enhanced CRC migration and invasion. Co-expressing either miR-34a/b had minimal to no effect on MAT2A/MAT2B’s ability to increase migration, invasion and growth. Taken together, MAT2A and MAT2B are important targets of miR-34a/b and SAMe and MTA target this axis, suppressing MAT2A/MAT2B while raising miR-34a/b expression, inhibiting cancer metastasis.
Highlights
MicroRNAs are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level [1]
We have shown SAMe and MTA lowered the expression of methionine adenosyltransferase 2A (MAT2A), which is overexpressed in human colorectal cancers (CRC) [7]
We examined whether SAMe and MTA treatment might influence miR-34a and miR-34b expression because they inhibit IL-6/Signal transducer and activator of transcription 3 (STAT3) activation [6], which inhibits miR34a expression [5], and they lower MAT2A expression [7], which contains possible binding sequences in its 3’UTR for miR-34a and miR-34b
Summary
MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level [1]. MiRNAs are deregulated in human cancers, with up-regulation of multiple oncogenic miRNAs and downregulation of tumor suppressor miRNAs [1]. MiR-34a is one of the tumor suppressor miRNAs that is down-regulated in multiple human cancers, including colorectal cancer (CRC), pancreas and prostate [1,2,3]. MiR-34 family members are transcriptional targets of p53 and p53 was shown to inhibit CRC metastasis by inducing miR-34a [5]. Using the same animal model, we reported S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) inhibited IL-6-STAT3 signaling and lowered tumor burden [6]. We have shown SAMe and MTA lowered the expression of methionine adenosyltransferase 2A (MAT2A), which is overexpressed in human CRC [7]
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