Amplification of MPZL1/PZR gene in hepatocellular carcinoma
Yao-Tsung Yeh1, Hong-Ying Dai1, Ching-Yen Chien1
11 Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, Taiwan ; 2 Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract:
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. It is noted that metastasis is a fundamental biological behavior of HCC and the main cause of treatment failure. The identification of somatic alterations and their specific inhibitors may contribute to reduce side effects and prolong patient survival in HCC. Chromosomal copy number alterations (CNAs) are important subclasses of somatic mutations and can be used as an effective method of identifying driver genes with causal roles in carcinogenesis. Jia et al. identified a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. They also found that MPZL1 may recruit the SHP-2 and subsequently activate/phosphorylate Src kinase at Tyr426, promoting phosphorylation of cortactin and migration of HCC cells. It is noted that phosphorylation of Tyr416 in the activation loop of the kinase domain up-regulates enzyme activity of Src. In addition, the active state of c-Src, p-Tyr416-c-Src, is an independent prognostic marker of poor patient survival in HCC. Therefore, c-Src signaling may be a druggable target and c-Src targeted therapy may improve patient outcome in this specific subtype of HCC patient with a gain of the recurrent focal amplicon, 1q24.1-24.2.
Insights
Researchers identified a new gene amplification in liver cancer (Hepatocellular carcinoma - HCC) that drives metastasis. Targeting the Src signaling pathway may offer a new treatment strategy for HCC patients with this specific genetic alteration.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hepatocellular carcinoma (HCC) is a major cause of cancer death globally.
- Metastasis is a key factor in HCC treatment failure.
- Somatic mutations, including chromosomal copy number alterations (CNAs), are crucial in carcinogenesis.
Purpose of the Study:
- To identify novel driver genes and potential therapeutic targets in HCC.
- To investigate the role of the 1q24.1-24.2 amplicon and its target gene, MPZL1, in HCC metastasis.
Main Methods:
- Analysis of chromosomal copy number alterations (CNAs) in HCC.
- Investigating the molecular interactions involving MPZL1, SHP-2, Src kinase, and cortactin.
- Assessing the prognostic significance of activated Src (p-Tyr416-c-Src).
Main Results:
- A novel recurrent focal amplicon, 1q24.1-24.2, was identified, targeting the MPZL1 gene in HCC.
- MPZL1 was found to recruit SHP-2, leading to Src kinase activation and subsequent phosphorylation of cortactin, promoting HCC cell migration.
- Phosphorylation of Tyr416 in c-Src (p-Tyr416-c-Src) is an independent prognostic marker for poor HCC patient survival.
Conclusions:
- The c-Src signaling pathway is implicated in HCC metastasis driven by the 1q24.1-24.2 amplicon.
- Targeting c-Src signaling represents a potential therapeutic strategy for HCC patients with this specific genetic alteration.
