The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma

Wang, Chaoqun; Dong, Liqian; Li, Xiaozhuang; Li, Yao; Bao, Zhenmin; Wu, Huibo; Shen, Benqiang; Ma, Panfei; Li, Zuoyu; Xu, Yang; Chen, Bangliang; Pan, Shangha; Fu, Yao; Huo, Zhongqi; Jiang, Hongchi; Wu, Yaohua; Ma, Yong

doi:10.1016/j.freeradbiomed.2020.11.035

“…ELL has been identified as a potential tumor suppressor by interacting with c-Myc and suppresses colon tumor xenograft growth ( Chen et al, 2016 ). It was found that MPC1 was downregulated in CRC and its low expression was correlated with poor prognosis; Mechanically, decreased MPC1 enhanced tumor metastasis by activating the Wnt/β-catenin pathway ( Wang et al, 2021 ). In addition, the function of few genes might not be consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis

Bu

¹

,

Huang

²

,

Li

³

et al. 2021

PeerJ

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Colorectal cancer (CRC) is one of the most common malignant carcinomas worldwide with poor prognosis, imposing an increasingly heavy burden on patients. Previous experiments and epidemiological studies have shown that vitamin D and vitamin D-related genes play a vital role in CRC. Therefore, we aimed to construct a vitamin D-related gene signature to predict prognosis in CRC. The CRC data from The Cancer Genome Atlas (TCGA) was performed as the training set. A total of 173 vitamin D-related genes in the TCGA CRC dataset were screened, and 17 genes associated with CRC prognosis were identified from them. Then, a vitamin D-related gene signature consisting of those 17 genes was established by univariate and multivariate Cox analyses. Moreover, four external datasets (GSE17536, GSE103479, GSE39582, and GSE17537) were used as testing set to validate the stability of this signature. The high-risk group presented a significantly poorer overall survival than low-risk group in both of training set and testing sets. Besides, the areas under the curve (AUCs) for signature on OS in training set at 1, 3, and 5 years were 0.710, 0.708, 0.710 respectively. The AUCs of the ROC curve in GSE17536 for 1, 3, and 5 years were 0.649, 0.654, and 0.694. These results indicated the vitamin D-related gene signature model could effectively predict the survival status of CRC patients. This vitamin D-related gene signature was also correlated with TNM stage in CRC clinical parameters, and the higher risk score from this model was companied with higher clinical stage. Furthermore, the high accuracy of this prognostic signature was validated and confirmed by nomogram model. In conclusion, we have proposed a novel vitamin D-related gene model to predict the prognosis of CRC, which will help provide new therapeutic targets and act as potential prognostic biomarkers for CRC.

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“…ELL has been identified as a potential tumor suppressor by interacting with c-Myc and suppresses colon tumor xenograft growth (Chen et al 2016). It was found that MPC1 was downregulated in CRC and its low expression was correlated with poor prognosis; Mechanically, decreased MPC1 enhanced tumor metastasis by activating the Wnt/β-catenin pathway (Wang et al 2021). In addition, the function of few genes might not be consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Peer Review #1 of "Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis (v0.1)"

Rathod¹

2021

0

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Colorectal cancer (CRC) is one of the most common malignant carcinomas worldwide with poor prognosis, imposing an increasingly heavy burden on patients. Previous experiments and epidemiological studies have shown that vitamin D and vitamin D-related genes play a vital role in CRC. Therefore, we aimed to construct a vitamin D-related gene signature to predict prognosis in CRC. The CRC data from The Cancer Genome Atlas (TCGA) was performed as the training set. A total of 173 vitamin D-related genes in the TCGA CRC dataset were screened, and 17 genes associated with CRC prognosis were identified from them. Then, a vitamin D-related gene signature consisting of those 17 genes was established by univariate and multivariate Cox analyses. Moreover, four external datasets (GSE17536, GSE103479, GSE39582, and GSE17537) were used as testing set to validate the stability of this signature. The high-risk group presented a significantly poorer overall survival than low-risk group in both of training set and testing sets. Besides, the areas under the curve (AUCs) for signature on OS in training set at 1, 3, and 5 years were 0.710, 0.708, 0.710 respectively. The AUCs of the ROC curve in GSE17536 for 1, 3, and 5 years were 0.649, 0.654, and 0.694. These results indicated the vitamin D-related gene signature model could effectively predict the survival status of CRC patients. This vitamin D-related gene signature was also correlated with TNM stage in CRC clinical parameters, and the higher risk score from this model was companied with higher clinical stage. Furthermore, the high accuracy of this prognostic signature was validated and confirmed by nomogram model. In conclusion, we have proposed a novel vitamin D-related gene model to predict the prognosis of CRC, which will help provide new therapeutic targets and act as potential prognostic biomarkers for CRC.

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“…Aberrant expression of MPC1 is also involved in cancer-associated metabolic dysregulation. For example, MPC1 regulates mitochondrial respiratory capacity in renal cell carcinoma (RCC) [ 37 ], prostate cancer [ 38 ], hepatocellular carcinoma (HCC) [ 39 ], and cholangiocarcinoma [ 40 ].…”

Section: Decreased Mpc1 Expression May Function In Tumour Progressionmentioning

confidence: 99%

“…In the liver, MPC1 binds nuclear respiratory factor 1 (NRF1) and promotes mitochondrial biogenesis. In HCC, a decrease in proliferator-activated receptor gamma coactivator-1 alpha(PGC1α)attenuates NRF1 and MPC1 expression, thus promoting HCC progression [ 39 ]. In prostate cancer, MPC1 deficiency significantly increases lactate production, glucose consumption, and glycolytic capacity [ 38 ].…”

Section: Decreased Mpc1 Expression May Function In Tumour Progressionmentioning

confidence: 99%

Mitochondrial pyruvate carrier 1: a novel prognostic biomarker that predicts favourable patient survival in cancer

Xue

¹

,

Li

²

,

Bao

³

et al. 2021

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Mitochondrial pyruvate carrier 1 (MPC1) is a key metabolic protein that regulates the transport of pyruvate into the mitochondrial inner membrane. MPC1 deficiency may cause metabolic reprogramming. However, whether and how MPC1 controls mitochondrial oxidative capacity in cancer are still relatively unknown. MPC1 deficiency was recently found to be strongly associated with various diseases and cancer hallmarks. We utilized online databases and uncovered that MPC1 expression is lower in many cancer tissues than in adjacent normal tissues. In addition, MPC1 expression was found to be substantially altered in five cancer types: breast-invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD). However, in KIRC, LUAD, PAAD, and PRAD, high MPC1 expression is closely associated with favourable prognosis. Low MPC1 expression in BRCA is significantly associated with shorter overall survival time. MPC1 expression shows strong positive and negative correlations with immune cell infiltration in thymoma (THYM) and thyroid carcinoma (THCA). Furthermore, we have comprehensively summarized the current literature regarding the metabolic reprogramming effects of MPC1 in various cancers. As shown in the literature, MPC1 expression is significantly decreased in cancer tissue and associated with poor prognosis. We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven oxidative phosphorylation (OXPHOS); and increased lactate production, glucose consumption, and glycolytic capacity, and the underlying mechanisms. These activities facilitate tumour progression, migration, and invasion. MPC1 is a novel cancer biomarker and potentially powerful therapeutic target for cancer diagnosis and treatment. Further studies aimed at slowing cancer progression are in progress.

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The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma

Cited by 28 publications

References 37 publications

Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis

Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis

Peer Review #1 of "Identification of Vitamin D-related gene signature to predict colorectal cancer prognosis (v0.1)"

Mitochondrial pyruvate carrier 1: a novel prognostic biomarker that predicts favourable patient survival in cancer

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