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PKM splice-switching ASOs induce upregulation of dual-specificity phosphatases and dephosphorylation of ERK1/2 in hepatocellular carcinoma

GSE274520 Homo sapiens (human) RNA-seq (gene expression) 15 samples Submitted 2025/08/09 Platform GPL11154
At a glance

RNA-seq (gene expression) · human · 15 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Topic
Hepatocellular carcinomaThis series is part of our curated briefing on it.
Samples
15 samples: 15 samples, each with a distinct title — no replicated groupsGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
PKM splice-switching ASOs induce upregulation of dual-specificity phosphatases and dephosphorylation of ERK1/2 in hepatocellular carcinomaThe Journal of biological chemistry · 2025
Summary (written by the submitters)
Pyruvate kinase M isoform 2 (PKM2) is preferentially expressed in nearly all cancers. It primarily functions as the last enzyme in glycolysis, but has other reported non-canonical functions, including recruiting transcription factors to oncogenes, and phosphorylating proteins. We previously described antisense oligonucleotides that disrupt alternative splicing of PKM pre-mRNA (PKM-ASOs), resulting in PKM2-to-PKM1 isoform switching in hepatocellular carcinoma (HCC), which reduces HCC growth.
Read the full summary ↓
PKM1 has higher enzymatic activity than PKM2, which potentially drives metabolism away from macromolecule synthesis, and may explain decreased HCC growth upon PKM-ASO treatment. As PKM-ASOs also reduce PKM2 levels, how PKM splice-switching inhibits HCC cell proliferation was unclear. Here, we characterized the individual consequences of altering PKM1 or PKM2 protein levels in HCC, and observed that reducing PKM2 alone was sufficient to decrease HCC cell proliferation, whereas overexpressing PKM1 had no effect. Moreover, increasing PK activity via a small-molecule PKM2 activator had no effect on HCC cell proliferation, suggesting that PKM-ASOs affect PKM2’s non-metabolic functions. Transcriptomic and RT-qPCR analyses of HCC cells treated with PKM-ASO or PKM2-siRNA revealed upregulation of dual-specificity phosphatase 2 (DUSP2) and other related DUSPs, which act directly on ERK1/2 in the MAPK signaling pathway. Luciferase reporter assays demonstrated that PKM-ASO treatment activated the DUSP2 promoter, which correlated with decreased ERK1/2 phosphorylation. Lenvatinib is a second-line HCC therapy that indirectly reduces ERK1/2 phosphorylation, and combined treatment with PKM-ASOs inhibited proliferation of HCC cells more than either treatment alone. In summary, our results reveal a mechanism by which PKM-ASOs affect PKM2 dependency in HCC.
Published in
PKM splice-switching ASOs induce upregulation of dual-specificity phosphatases and dephosphorylation of ERK1/2 in hepatocellular carcinoma
Voss DM, Kral AJ, Sim G et al. · The Journal of biological chemistry 2025 · PMID 39993527 · doi:10.1016/j.jbc.2025.108345
This dataset
Open GSE274520 in finder → Find more human RNA-seq datasets → Hepatocellular carcinoma landscape →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE274520_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1145569 and SRA study SRP524859. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 39993527) ↗
Study design
15 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 15 sample titles: 15 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
More Hepatocellular carcinoma datasets

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