The RAS oncogene in brain tumors - let-7 microRNA involvement

Sep 21, 2026

RAS oncogenes act as master regulators across many cancers, yet brain tumors are often not clearly RAS-driven due to the rarity of RAS mutations and the lack of dominant actionable alterations in glioblastoma. Standard glioma management still relies on maximal resection, radiotherapy, and chemotherapy, while genomic convergence at the RAS/MAPK axis remains important in gliomagenesis. microRNAs regulate carcinogenesis, and let-7 functions as a tumor-suppressive miRNA that directly downregulates multiple oncogenes, including RAS family members. let-7 activity affects glioma malignancy and modulates GBM sensitivity to therapy, and this review summarizes how let-7 interacts with KRAS in brain tumor oncogenesis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages8

Reading Time20 min

AccessFree to download

Abstract

Introduction

MicroRNAs and cancer relevance

let-7 as a tumor suppressor

Inhibition of glioma malignancy

Context-dependent roles of let-7

KRAS regulation and let-7 interaction

Molecular Biology Reports (2024) 51:531 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1033-024-09439-z The RAS oncogene in brain tumors and the involvement of let‑7 microRNA Samantha Messina1 Received: 6 July 2023 / Accepted: 11 March 2024 / Published online: 18 April 2024 © The Author(s) 2024 Abstract RAS oncogenes are master regulator genes in many cancers. In general, RAS-driven cancers have an oncogenicRAS mutation that promotes disease progression (colon, lung, pancreas). In contrast, brain tumors are not necessarily RAS-driven cancers because RAS mutations are rarely observed. In particular, glioblastomas (the most lethal brain tumor) do not appear to have dominant genetic mutations that are suitable for targeted therapy. Standard treatment for most brain tumors continues to focus on maximal surgical resection, radiotherapy and chemotherapy. Yet the convergence of genomic aberrations such as EGFR, PDGFR and NF1 (some of which are clinically effective) with activation of the RAS/MAPK cascade is still considered a key point in gliomagenesis, and KRAS is undoubtedly a driving gene in gliomagenesis in mice. In cancer, microRNAs (miRNA) are small, non-coding RNAs that regulate carcinogenesis. However, the functional consequences of aberrant miRNA expression in cancer are still poorly understood. let-7 encodes an intergenic miRNA that is classified as a tumour suppressor, at least in lung cancer. Let-7 suppresses a plethora of oncogenes such as RAS, HMGA, c-Myc, cyclin-D and thus suppresses cancer development, differentiation and progression. let-7 family members are direct regulators of certain RAS family genes by binding to the sequences in their 3′untranslated region (3′UTR) . let-7 miRNA is involved in the malignant behaviour in vitro—proliferation, migration and invasion—of gliomas and stem-like glioma cells as well as in vivo models of glioblastoma multiforme (GBM) via KRAS inhibition. It also increases resistance to certain chemotherapeutic agents and radiotherapy in GBM. Although let-7 therapy is not yet established, this review updates the current state of knowledge on the contribution of miRNA let-7 in interaction with KRAS to the oncogenesis of brain tumours. Keywords RAS oncogenes · Let-7 miRNA · Brain tumor Abbreviations miRNA MicroRNA let-7 Lethal-7 GBM Glioblastoma MB Medulloblastoma SHH Sonic Hedgehog-activated DIPG Diffuse intrinsic pontine gliomas NF1 Neurofibromin 1 PDGFR Platelet-derived growth factor receptor EGFR Epidermal growth factor receptor DMG Diffuse midline glioma * Samantha Messina [samantha.messina@uniroma3.it](samantha.messina@uniroma3.it) 1 Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146 Rome, Italy Introduction MicroRNAs (miRNAs) are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. In general, aberrant expression of microRNAs has been linked to all human cancers. miRNAs are dysregulated in a plethora of diseases, including cancers; poorly differentiated tumors displayed lower miRNA expression compared to tumors with a higher differentiation. The Slack laboratory showed one of the first pieces of evidence that lethal-7 (let- 7) plays a key role in cancer. By showing that RAS is regulated by the let-7 miRNA family in Caenorhabditis elegans and by highlighting let-7 complementary sites in human RAS 3 ′UTRs, they first validated that the let-7 miRNA family negatively regulates RAS in two different C. elegans tissues and human cell lines and lung tissue. This was the first report of the mechanism of action of a miRNA acting as a tumor suppressor [1, 2] . The heterochronic miRNA let-7 display tumor suppressive properties at least in lung, colon, breast, and leukemia cancers. It is categorized as a tumor suppressor because it reduces cancer aggressiveness, chemoresistance, and radioresistance. Particularly, studies inferred from human cancer databases report let-7 family me

FAQs

Why are many brain tumors not considered RAS-driven cancers?

RAS mutations are rarely observed in brain tumors, and glioblastomas do not show dominant genetic mutations that readily support targeted therapy.

What roles does let-7 play in cancer and gliomas?

let-7 is classified as a tumor suppressor and suppresses multiple oncogenes, including RAS family genes. It inhibits malignant behaviors of glioma cells and stem-like glioma cells and acts through KRAS inhibition in in vivo GBM models.

How might let-7 influence treatment response in glioblastoma?

let-7 involvement is linked to increased resistance of GBM to certain chemotherapeutic agents and radiotherapy, and the review summarizes the current state of knowledge on this interaction.

Sep 21, 2026

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