Midline 1 interacting protein 1 promotes cancer metastasis through FOS-like 1-mediated matrix metalloproteinase 9 signaling in HCC.

Abstract

BACKGROUND AND AIMS:

Understanding the mechanisms of HCC progression and metastasis is crucial to improve early diagnosis and treatment. This study aimed to identify key molecular targets involved in HCC metastasis.

APPROACH AND RESULTS:

Using whole-transcriptome sequencing of patients' HCCs, we identified and validated midline 1 interacting protein 1 (MID1IP1) as one of the most significantly upregulated genes in metastatic HCCs, suggesting its potential role in HCC metastasis. Clinicopathological correlation demonstrated that MID1IP1 upregulation significantly correlated with more aggressive tumor phenotypes and poorer patient overall survival rates. Functionally, overexpression of MID1IP1 significantly promoted the migratory and invasive abilities and enhanced the sphere-forming ability and expression of cancer stemness-related genes of HCC cells, whereas its stable knockdown abrogated these effects. Perturbation of MID1IP1 led to significant tumor shrinkage and reduced pulmonary metastases in an orthotopic liver injection mouse model and reduced pulmonary metastases in a tail-vein injection model in vivo . Mechanistically, SP1 transcriptional factor was found to be an upstream driver of MID1IP1 transcription. Furthermore, transcriptomic sequencing on MID1IP1-overexpressing HCC cells identified FOS-like 1 (FRA1) as a critical downstream mediator of MID1IP1. MID1IP1 upregulated FRA1 to subsequently promote its transcriptional activity and extracellular matrix degradation activity of matrix metalloproteinase MMP9, while knockdown of FRA1 effectively abolished the MID1IP1-induced migratory and invasive abilities.

CONCLUSIONS:

Our study identified MID1IP1 as a regulator in promoting FRA1-mediated-MMP9 signaling and demonstrated its role in HCC metastasis. Targeting MID1IP1-mediated FRA1 pathway may serve as a potential therapeutic strategy against HCC progression.

• Authors: Yung-Tuen Chiu, Abdullah Husain, Karen Man-Fong Sze, Daniel Wai-Hung Ho, Eliana Mary Senires Suarez, Xia Wang, Eva Lee, Hoi-Tang Ma, Joyce Man-Fong Lee, Lo-Kong Chan, Irene Oi-Lin Ng
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 78 Issue 5 Pg. 1368-1383 (11 01 2023) ISSN: 1527-3350 [Electronic] United States
• PMID: 36632999 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

Chemical References

• Matrix Metalloproteinase 9
• SP1 protein, human
• MID1IP1 protein, human
• fos-related antigen 1
• MMP9 protein, human

Topics

• Animals
• Humans
• Mice
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Liver Neoplasms (genetics, metabolism, pathology)
• Lung Neoplasms (genetics, secondary)
• Matrix Metalloproteinase 9 (metabolism)
• Neoplasm Metastasis
• Signal Transduction (genetics)