Abstract
Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule‐associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence‐free survival (RFS). OPTN KO cells proliferated relatively slower versus wild‐type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta‐oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production.
Highlights
Hepatocellular carcinoma (HCC) is the fourth and sixth leading causes, respectively, of cancer-related mortality and morbidity worldwide.[1]
Among these autophagy adaptor proteins, optineurin (OPTN) recruits light chain 3 (LC3) to autophagosome in selective autophagic processes such as aggrephagy, mitophagy, and xenophagy.[19]
The overall survival (OS) and DFS of LC3-negative patients with HCC were not significantly different compared with those with high or low levels of OPTN (Figure S2C and D). These results suggest that OPTN contributes to the progression of HCC through an autophagic mechanism
Summary
Hepatocellular carcinoma (HCC) is the fourth and sixth leading causes, respectively, of cancer-related mortality and morbidity worldwide.[1]. These adaptor proteins recognize substrates for efficient autophagy.[18] the mechanism underlying the effects of adaptor protein on mitophagy during cancer progression is unknown Among these autophagy adaptor proteins, optineurin (OPTN) recruits LC3 to autophagosome in selective autophagic processes such as aggrephagy, mitophagy, and xenophagy.[19] Mutation of OPTN are associated with normal tension glaucoma and amyotrophic lateral sclerosis.[20] OPTN accelerates the autophagic activities of lung cancer and gastric cancer cells,[21] and the suppression of OPTN expression reduces the cell division.[22] In contrast, to the best of our knowledge, the role of OPTN in the progression of HCC through mitophagic activity is unknown. To fill this gap in our knowledge, here we assessed the effects of OPTN expression on the progression of HCC
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