Expression of Mitophagy-Associated Factors and Their Associations with Metastasis and Prognosis in Oral Squamous Cell Carcinoma.

Abstract

Background/objectives: Mitophagy-associated factors have been implicated in tumor behavior and patient outcomes; however, their clinical significance depends on tumor type, stage, and microenvironmental context, and consistent conclusions remain lacking. We aimed to comprehensively assess the expression of mitophagy-associated factors in a moderate-sized cohort of patients with oral squamous cell carcinoma (OSCC) and clarify their prognostic significance.

Methods: A retrospective cohort study included 197 patients with OSCC who underwent primary surgical resection between August 2013 and October 2018. Immunohistochemical expression of mitophagy-associated factors, including transcription factor EB (TFEB), nuclear factor erythroid 2-related factor 2 (NRF2), activating transcription factor 4 (ATF4), Parkin, PTEN-induced kinase 1 (PINK1), and mitochondrial ubiquitin ligase (MITOL), was evaluated. Associations between protein expression and clinicopathological parameters, local control, 5-year disease-specific survival (DSS), regional control, and distant metastasis were analyzed.

Results: High expression of NRF2 and TFEB was significantly related with decreased DSS, poor regional control, and increased distant metastasis. High ATF4 expression was associated with distant metastasis and showed no association with DSS. Parkin, PINK1, and MITOL showed no significant association with patient outcomes. Explanatory multivariable analysis showed associations between high TFEB expression, vascular invasion, extranodal extension, and disease-specific mortality.

Conclusions: TFEB expression showed an exploratory association with aggressive tumor behavior and poor prognosis in OSCC, warranting further investigation. However, because immunohistochemical evaluation measures protein expression rather than mitophagy flux or mitochondrial turnover, these findings represent associations between mitophagy-associated factor expression and clinical outcomes and do not directly demonstrate altered mitophagy activity.