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

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• 5-Fluorouracil (5FU) is a chemotherapy drug targeting thymidylate synthase (TYMS), crucial for DNA replication.
• Drug resistance, often due to high TYMS levels, limits 5FU efficacy in cancer treatment.
• Non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are implicated in regulating TYMS expression.

Purpose of the Study:

• To elucidate the regulatory network of miRNAs and lncRNAs controlling TYMS protein levels.
• To understand how this network contributes to 5FU resistance in cancer.

Main Methods:

• Identification of miRNAs targeting TYMS mRNA in colon cancer.
• Analysis of lncRNA (MALAT1) regulation of these miRNAs.
• Investigation of potential feedback loops involving MALAT1, miRNAs, and cancer-related pathways (YAP1/TCF4/β-catenin).

Main Results:

• Several miRNAs targeting TYMS mRNA were identified, with their regulation influenced by MALAT1.
• MALAT1 experimentally downregulates specific miRNAs (miR-197-3p, miR-203a-3p, miR-375-3p), which are reduced in cancers.
• A potential positive feedback loop involving MALAT1, YAP1, and miR-375-3p was proposed, potentially increasing MALAT1 expression in certain cancers.

Conclusions:

• The identified non-coding RNA network can upregulate thymidylate synthase levels.
• This upregulation may lead to reduced sensitivity of cancer cells to 5FU treatment, contributing to therapeutic failure.