Mitochondrial-Associated Protein LRPPRC is Related With Poor Prognosis Potentially and Exerts as an Oncogene Via Maintaining Mitochondrial Function in Pancreatic Cancer.

Li Wang,Yuchen Li,Yanrong Lu,Yi Zhang,Qiong-Ying Hu,Ziyi Zhao,Jun Luo,Bole Tian

doi:10.3389/fgene.2021.817672

Abstract

Background: The mitochondrial-associated protein leucine-rich pentatricopeptide repeat-containing (LRPPRC) exerts multiple functions involved in physiological processes, including mitochondrial gene translation, cell cycle progression, and tumorigenesis. Previously, LRPPRC was reported to regulate mitophagy by interacting with Bcl-2 and Beclin-1 and thus modifying the activation of PI3KCIII and autophagy. Considering that LRPPRC was found to be negatively associated with survival rate, we hypothesize that LRPPRC may be involved in pancreatic cancer progression via its regulation of autophagy. Methods: Real-time quantitative polymerase chain reaction was performed to detect the expression of LRPPRC in 90 paired pancreatic cancer and adjacent tissues and five pancreatic cancer cell lines. Mitochondrial reactive oxidative species level and function were measured. Mitophagy was measured by performing to detect LC3 levels. Results: By performing a real-time quantitative polymerase chain reaction, the association of LRPPRC with the prognosis of pancreatic cancer was established, and pancreatic cancer tissues had significantly higher LRPPRC expression than adjacent tissues. LRPPRC was negatively associated with the overall survival rate. LRPPRC was also upregulated in pancreatic cancer cell lines. Knockdown of LRPPRC promoted reactive oxidative species accumulation, decreased mitochondrial membrane potential, promoted autophagy/mitophagy, and induced mitochondrial dysfunction. Subsequently, knockdown of LRPPRC inhibited malignant behaviors in PANC-1 cells, including proliferation, migration, invasion, tumor formation, and chemoresistance to gemcitabine. Finally, by inhibiting autophagy/mitophagy using 3-MA, the inhibitory effect of LRPPRC knockdown on proliferation was reversed. Conclusion: Taken together, our results indicate that LRPPRC may act as an oncogene via maintaining mitochondrial homeostasis and could be used as a predictive marker for patient prognosis in pancreatic cancer.

Highlights

Pancreatic cancer is one of the leading causes of cancer-related death and has a very low overall survival rate of approximately 5% and a median survival of less than 6 months (Siegel et al, 2012)
Leucine-rich pentatricopeptide repeat-containing (LRPPRC) was reported to be associated with mitochondria by interacting with Parkin and stabilizing Parkin substrates, including Bcl-2 and Parkin itself to inhibit autophagy, and LRPPRC protects mitochondria from autophagy degradation (Zou et al, 2013)
We found that knockdown of LRPPRC, Bcl-2, Beclin-1, and PI3K or blockage of autophagy with 3-MA decreased autophagy/ mitophagy and adenosine triphosphate (ATP) synthesis

Summary

Introduction

Pancreatic cancer is one of the leading causes of cancer-related death and has a very low overall survival rate of approximately 5% and a median survival of less than 6 months (Siegel et al, 2012). LRPPRC was reported to be associated with mitochondria by interacting with Parkin and stabilizing Parkin substrates, including Bcl-2 and Parkin itself to inhibit autophagy, and LRPPRC protects mitochondria from autophagy degradation (Zou et al, 2013). Knockdown of LRPPRC causes a decrease in Bcl-2, followed by Beclin-1 release to form complexes with PI3KCIII to activate basal levels of autophagy (Zou et al, 2014). In this manner, LRPPRC acts as an autophagy/mitophagy inhibitor via maintaining mitochondrial membrane potential (MMP) and promoting mitochondrial function (Blackstone, 2015). The mitochondrial-associated protein leucine-rich pentatricopeptide repeat-containing (LRPPRC) exerts multiple functions involved in physiological processes, including mitochondrial gene translation, cell cycle progression, and tumorigenesis. Considering that LRPPRC was found to be negatively associated with survival rate, we hypothesize that LRPPRC may be involved in pancreatic cancer progression via its regulation of autophagy

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Discussion

Conclusion