Metabolic changes during malignant transformation in primary cells of oral lichen planus: Succinate accumulation and tumour suppression.

Qiaozhen Yang,Xuedi Yu,Bin Guo,Xiaxia Wang,Hongying Sun,Saiyin Hexige,Jie Zhang

doi:10.1111/jcmm.14376

Qiaozhen Yang, Xuedi Yu + Show 5 more

Open Access

https://doi.org/10.1111/jcmm.14376

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Abstract

Oral squamous cell carcinoma (OSCC) is usually diagnosed at late stages, which leads to high morbidity. There are evidence that chronic inflammation (eg oral lichen planus [OLP]) was a risk factor of OSCC, but often misdiagnosed or ignored until invasion and metastasis. By applying precision medicine, the molecular microenvironment variations and relevant biomarkers for the malignant transformation from OLP to OSCC can be fully investigated. Several studies pointed out that the metabolic pathway were suppressed in OSCC. However, it remains unclear how the systemic profile of the metabolites change during the malignant transformation. In this study, we examined and compared the mucosa samples from 11 healthy individuals, 10 OLP patients and 21 OSCC patients. Based on the results, succinate, a key metabolite of the tricarboxylic acid cycle pathway, was accumulated in the primary cultured precancerous OLP keratinocytes and OSCC cells. Then, we found that succinate activated the hypoxia‐inducible factor‐1 alpha (HIF‐1α) pathway and induced apoptosis, which could also be up‐regulated by the tumour suppressor lncRNA MEG3. These results suggested the critical roles of succinate and MEG3 in the metabolic changes during malignant transformation from OLP to OSCC, which indicated that succinate, HIF1α and downstream proteins might serve as new biomarkers of precancerous OLP for early diagnosis and therapeutic monitoring. In addition, succinate or its prodrugs might become a potential therapy for the prevention or treatment of OSCC.

Highlights

Oral squamous cell carcinoma (OSCC) holds 95% of all types of head and neck cancer, and the morbidity increased 50% over the last decade.[1]
Our study suggested that the MEG3-SUC-HIF-1α pathway-induced apoptosis might act as a protection against malignant transformation, which made SUC administration has a potential therapy for the prevention or treatment of OSCC
We found SUC, an important metabolite of TAC, played pivotal roles in the malignant transformation from oral lichen planus (OLP) to OSCC

Summary

| INTRODUCTION

Oral squamous cell carcinoma (OSCC) holds 95% of all types of head and neck cancer, and the morbidity increased 50% over the last decade.[1]. Yang et al[5] assessed genome-wide transcriptional profiles of OLP and OSCC by high-throughput sequencing and enrichment analyses of mRNAs and long noncoding RNAs (lncRNAs), which turned out that keratinization and MHC class I antigen processing were activated during the malignant transformation. Another carcinogenesis genome-wide analysis by Tang et al[9] indicated decreased expression of metabolic pathways in OSCC, such as the tricarboxylic acid (TCA cycle). Our study suggested that the MEG3-SUC-HIF-1α pathway-induced apoptosis might act as a protection against malignant transformation, which made SUC administration has a potential therapy for the prevention or treatment of OSCC. SUC, HIF-1α and downstream proteins could serve as new biomarkers for the diagnosis of OLP malignant transformation

| MATERIALS AND METHODS

Findings

| DISCUSSION