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

## TL;DR

This study shows how HIF-1α reduces SNPH levels in colorectal cancer, promoting liver metastasis through mitochondrial changes and cell movement.

## Contribution

The novel finding is the HIF-1α/miR-130a-3p/SNPH axis regulating CRC liver metastasis via mitochondrial dynamics and ROS.

## Key findings

- Low SNPH expression correlates with poor CRC prognosis and promotes cell migration and invasion.
- HIF-1α activates miR-130a-3p, which targets SNPH mRNA to reduce its levels and enhance metastasis.
- SNPH overexpression inhibits liver metastasis by promoting mitochondrial fusion and reducing ROS.

## 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.