What question did this study set out to answer?

Investigate how HIF-1α affects SNPH expression and its impact on liver metastasis in colorectal cancer.

March 28, 2026Open Access

HIF-1α suppresses SNPH expression to facilitate liver metastasis of colorectal cancer through regulating mitochondrial dynamics and filopodia formation

Key Points

Investigate how HIF-1α affects SNPH expression and its impact on liver metastasis in colorectal cancer.
Analyzed multiple transcriptomic data sets to assess SNPH expression and prognosis in CRC patients.
Performed luciferase reporter assays to study HIF-1α's regulation of miR-130a-3p expression.
Assessed the effects of SNPH knockdown on mitochondrial dynamics and filopodia formation.
Used in vivo models to evaluate the impact of SNPH on liver metastasis of CRC cells.
Low SNPH expression correlates with poor prognosis in CRC patients.
SNPH knockdown enhanced cell migration and invasion by increasing filopodia formation.
HIF-1α transcriptionally activates miR-130a-3p, which inhibits SNPH expression.
Overexpression of SNPH led to increased mitochondrial fusion and reduced liver metastasis in vivo.

Abstract

Abstract Colorectal cancer (CRC) is a leading cause of cancer-associated deaths, with liver metastases developing in about 50% of patients. Mitochondrial dynamics play critical roles in a diverse range of cellular functions, including cell migration and cancer metastasis. However, the influence of mitochondrial dynamics deregulation in CRC liver metastasis is incompletely understood. Through multiple transcriptomic data analysis and validation, we found that low expression of SNPH significantly correlated with poor prognosis of CRC patients. SNPH knockdown altered mitochondrial dynamics to increase cell migration and invasion by promoting filopodia formation. Moreover, the reduced levels of SNPH were linked to HIF-1α expression. Luciferase reporter assay revealed that HIF-1α transcriptionally activated miR-130a-3p expression, which targeted SNPH mRNA to inhibit its protein levels. Furthermore, miR-130a-3p inhibitor suppressed SNPH downregulation, filopodia formation, and CRC cells metastasis under hypoxic conditions. Mechanistically, SNPH downregulation promoted ROS production, resulting in the activation of the AKT/cdc42 pathway and downstream PAK1/Cofilin cascade. The overexpression of SNPH increased mitochondrial fusion and deterred the liver metastasis ability of CRC cells in vivo. Together, our results suggest that SNPH suppression imposed by the HIF-1α/miRNA-130a-3p axis under hypoxia conditions promotes the liver metastasis of CRC cells by activating the AKT/cdc42-PAK1/Cofilin cascade through mitochondrial dynamics-mediated ROS production.

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