MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma

New, Maria I.; Acker, Tim Van; Sakamaki, Jun-Ichi; Jiang, Ming; Saunders, Rebecca E.; Long, Jaclyn; Wang, Victoria M.-Y.; Behrens, Axel; Cerveira, Joana; Sudhakar, Padhmanand; Jefferies, Harold B.J.; Ryan, Kevin M.; Howell, Michael; Tooze, Sharon A.

doi:10.1158/0008-5472.can-18-2553

Cited by 31 publications

(26 citation statements)

References 43 publications

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“…In pancreatic ductal adenocarcinoma (PDAC), the knockdown of MDH1 or inhibition of its activity could repress mitochondria respiration and influence glutamine metabolism, which enhances tumor cells' sensitivity to oxidative stress and suppresses proliferation [50]. Moreover, as a novel regulator of autophagy, MDH1 is required for autophagosome formation in the early stages of autophagy to maintain pancreatic tumor cell survival [51]. Here, we found that MDH1 is downregulated at the mRNA level in GBM based on the TCGA RNA sequencing data.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of RNA-Binding Proteins in Glioma

Wang

Tang

Yuan

et al. 2020

Cancers

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RNA-binding proteins (RBPs) play important roles in many cancer types. However, RBPs have not been thoroughly and systematically studied in gliomas. Global analysis of the functional impact of RBPs will provide a better understanding of gliomagenesis and new insights into glioma therapy. In this study, we integrated a list of the human RBPs from six sources—Gerstberger, SONAR, Gene Ontology project, Poly(A) binding protein, CARIC, and XRNAX—which covered 4127 proteins with RNA-binding activity. The RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) (n = 699) and Chinese Glioma Genome Atlas (CGGA) (n = 325 + 693). We examined the differentially expressed genes (DEGs) using the R package DESeq2, and constructed a weighted gene co-expression network analysis (WGCNA) of RBPs. Furthermore, survival analysis was also performed based on the univariate and multivariate Cox proportional hazards regression models. In the WGCNA analysis, we identified a key module involved in the overall survival (OS) of glioblastomas. Survival analysis revealed eight RBPs (PTRF, FNDC3B, SLC25A43, ZC3H12A, LRRFIP1, HSP90B1, HSPA5, and BNC2) are significantly associated with the survival of glioblastoma patients. Another 693 patients within the CGGA database were used to validate the findings. Additionally, 3564 RBPs were classified into canonical and non-canonical RBPs depending on the domains that they contain, and non-canonical RBPs account for the majority (72.95%). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that some non-canonical RBPs may have functions in glioma. Finally, we found that the knockdown of non-canonical RBPs, PTRF, or FNDC3B can alone significantly inhibit the proliferation of LN229 and U251 cells. Simultaneously, RNA Immunoprecipitation (RIP) analysis indicated that PTRF may regulate cell growth and death- related pathways to maintain tumor cell growth. In conclusion, our findings presented an integrated view to assess the potential death risks of glioblastoma at a molecular level, based on the expression of RBPs. More importantly, we identified non-canonical RNA-binding proteins PTRF and FNDC3B, showing them to be potential prognostic biomarkers for glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Integrated Analysis of RNA-Binding Proteins in Glioma

Wang

Tang

Yuan

et al. 2020

Cancers

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“…Although the relationship between FCGR2B and prognosis in sarcoma patients had not been reported, the prognostic value of FCGR2B had been widely confirmed in other cancers, such as hepatocellular carcinoma and glioblastoma [ 36 , 42 ]. In addition, New M et.al [ 37 ] demonstrated that MPP7 is novel regulators of autophagy, which was thought to be responsible for the prognosis of pancreatic ductal adenocarcinoma. CYP2S1, described as Cytochrome P450 Family 2 Subfamily S Member 1, was reported significantly associated with colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of prognostic tumor microenvironment-related genes in osteosarcoma patients

Liu

Tian

et al. 2020

BMC Cancer

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Background Tumor microenvironment (TME) plays an important role in malignant tumors. Our study aimed to investigate the effect of the TME and related genes in osteosarcoma patients. Methods Gene expression profiles and clinical data of osteosarcoma patients were downloaded from the TARGET dataset. ESTIMATE algorithm was used to quantify the immune score. Then, the association between immune score and prognosis was studied. Afterward, a differential analysis was performed based on the high- and low-immune scores to determine TME-related genes. Additionally, Cox analyses were performed to construct two prognostic signatures for overall survival (OS) and disease-free survival (DFS), respectively. Two datasets obtained from the GEO database were used to validate signatures. Results Eighty-five patients were included in our research. The survival analysis indicated that patients with higher immune score have a favorable OS and DFS. Moreover, 769 genes were determined as TME-related genes. The unsupervised clustering analysis revealed two clusters were significantly related to immune score and T cells CD4 memory fraction. In addition, two signatures were generated based on three and two TME-related genes, respectively. Both two signatures can significantly divide patients into low- and high-risk groups and were validated in two GEO datasets. Afterward, the risk score and metastatic status were identified as independent prognostic factors for both OS and DFS and two nomograms were generated. The C-indexes of OS nomogram and DFS nomogram were 0.791 and 0.711, respectively. Conclusion TME was associated with the prognosis of osteosarcoma patients. Prognostic models based on TME-related genes can effectively predict OS and DFS of osteosarcoma patients.

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“…Another link between autophagy and PDAC cancer stem cells is YAP/TAZ-signaling, shown to be required for cell dedifferentiation and the acquisition of self-renewing properties, i.e., stem cell formation [29]. YAP/TAZ has also been shown to be a positive autophagy regulator [30], and promotes autophagic flux by increasing Armus expression, a RAB7-GAP required for autophagosome turnover [29]. The role of autophagy in PDAC survival is not limited to tumor cells alone, but extends to the tumor microenvironment.…”

Section: Conflicting Roles Of Autophagy In Pdacmentioning

confidence: 99%

The Role of Autophagy in Pancreatic Cancer—Recent Advances

New

Tooze

2019

Biology

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.

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MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma

Cited by 31 publications

References 43 publications

Integrated Analysis of RNA-Binding Proteins in Glioma

Integrated Analysis of RNA-Binding Proteins in Glioma

Comprehensive analysis of prognostic tumor microenvironment-related genes in osteosarcoma patients

The Role of Autophagy in Pancreatic Cancer—Recent Advances

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