Abstract
Several studies have indicated the biological role of mitochondrial Ca2+ uptake in cancer pathophysiology; however, its implications in predicting the prognosis of hepatocellular carcinoma (HCC) are not yet fully understood. Here, we collected tumor specimens and adjacent normal liver tissues from 354 confirmed HCC patients and analyzed the levels of cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB), mitochondrial calcium uniporter (MCU), mitochondrial calcium uptake 1 and 2 (MICU1, MICU2) using bioinformatics, qRT-PCR, and immunohistochemistry (IHC), and their relationship with clinicopathological characteristics and prognosis. HCC patients with low CREB/MICU1 and high MCU/MICU2 expression exhibited poor survival rate and prognosis in overall survival (OS) and disease-free survival (DFS) analyses. Low CREB/MICU1 and low MICU1 alone indicated poor prognosis in stage I/II and III/IV patients, respectively. In the poor differentiation/undifferentiation group, low expression of MICU1 indicated poor clinical outcomes. Low CREB/MICU1 expression suggested poor outcomes in patients with or without hepatitis B virus (HBV) infection and poor prognosis in the HCV infection group. In the non- hepatitis C virus (HCV) infection group, low MCU1 indicated a poor prognosis. Multivariate analysis demonstrated that CREB and MICU1 expression showed prognostic significance. This study demonstrates the prognostic significance of CREB, MCU, MICU1, and MICU2, in predicting HCC outcomes. Low CREB/MICU1 and high MCU/MICU2 in HCC tissues are associated with poor prognosis, thus offering a novel perspective in the clinical management for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for approximately 841,000 new cases and Biomedicines 2020, 8, 451; doi:10.3390/biomedicines8110451 www.mdpi.com/journal/biomedicines782,000 deaths [1]
This study demonstrates the prognostic significance of cyclic adenosine monophosphate response element-binding protein (CREB), mitochondrial calcium uniporter (MCU), MICU1, and MICU2, in predicting
Low CREB/MICU1 and high MCU/MICU2 in hepatocellular carcinoma (HCC) tissues are associated with poor prognosis, offering a novel perspective in the clinical management for HCC patients
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for approximately 841,000 new cases and Biomedicines 2020, 8, 451; doi:10.3390/biomedicines8110451 www.mdpi.com/journal/biomedicines782,000 deaths [1]. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for approximately 841,000 new cases and Biomedicines 2020, 8, 451; doi:10.3390/biomedicines8110451 www.mdpi.com/journal/biomedicines. In 2018, HCC became the fifth most common cancer with the second-highest mortality rate worldwide [2]. Mitochondria are vital cell organelles serving as the intracellular power plant regulating cellular life and death, that are actively involved in cellular Ca2+ signaling [4]. Mitochondria accumulate Ca2+ and have a ubiquitous physiological and pathophysiological role in Ca2+ handling [5]. Ca2+ accumulation within the mitochondria regulates the intrinsic functions of the organelle. One of the most characteristic roles of mitochondrial Ca2+ uptake is in the control of metabolic activity. Mitochondrial Ca2+ modulates the production of reactive oxygen species (ROS) critical for carcinogenesis and drug resistance in HCC [8]
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