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Table 1 Summary of the key characteristics of the selected studies

From: Alterations in PGC1α expression levels are involved in colorectal cancer risk: a qualitative systematic review

Title First Author Year Primary results Conclusion
Overexpression of PGC1-alpha enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein. Sung-Won Shin 2014 1) PGC-1α accelerates proliferation of HEK293 and CT-26 cells. 2) Knockdown of PGC1-α expression results in decreased cell proliferation of human colorectal cancer cells. 3) PGC-1α promotes the oncogenic potential of HEK293 cells. 4) PGC-1αoverexpressing HEK293 cells have decreased sensitivity to oxidative stress. PGC-1α overexpression upregulates proliferation of HEK293 and CT26 cells. In addition, this expression correlates with enhanced tumorigesis. Moreover, PGC-1α siRNA transfection resulted in decreased cell proliferation. Further studies to clarify the molecular interactions are needed.
PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine Elena Bellafante 2014 1) PGC-1β Is Highly Expressed in the Intestinal Epithelium and Modulates Intestinal Morphology. 2) Intestinal PGC-1β Overexpression Enhances Antioxidant Defense. 3) Intestinal PGC-1β Overexpression Promotes Intestinal Carcinogenesis. PGC-1β seems to act as an adaptive self-point regulator, capable of providing a balance between mitochondrial activity and production of increased reactive oxygen species.
Mitochondria and Tumor Progression in Ulcerative Colitis Cigdem Himmetoglu Ussakli 2013 1) Comparison of COX in No dysplastic Biopsies of UC Progressors and Nonprogressors show that tumor development could be due to previous lower COX levels. 2) Cox levels increase after the tumor development (Bimodal pattern). Mitochondria follow the same pattern. 3) PGC1α may drive of the mitochondrial changes observed. 1) At the biomarker level, COX loss precedes tumor progression in UC. 2) At the biological level, the loss of COX represents a reduction in the number of mitochondria in preneoplasia, which is restored in cancers. It appears to be driven by PGC1α.
PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Kavita Bhalla 2011 1) Loss of PGC1 protects against both colon and liver tumorigenesis. 2) Overexpression PGC1α promotes tumor growth in vivo. 3) PGC1α mediated induction of fatty acid synthesis promotes tumor growth. 1) Novel role for PGC1α in promoting carcinogenesis and tumor growth. 2) PGC1α coordinates the induction of a gene expression program that facilitates the conversion of glucose to fatty acids. 3) PGC1α is a potential therapeutic target for chemoprevention.
Bax is necessary for PGC1α pro-apoptotic effect in colorectal cancer cells Ilenia D’Errico 2011 1) PGC1α induces Bax activation. 2) PGC1α increases mitochondrial activity. 3) PGC1α induces apoptosis in the presence of Bax, but not without Bax. 4) PGC1α inhibits tumor growth in presence of Bax. 1) In the presence of Bax, the PGC1α-induced accumulation of reactive oxygen species is one of the main apoptosis-driving factors in CRC cells. 2) PGC1α is able to induce Bax activation and translocation to mitochondria, thus leading to apoptotic cascade.
PGC-1α/β upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations Sarika Srivastava 2007 1) PGC-1α and PGC-1β are markedly upregulated in V425. 2) Overexpression of PGC-1α and PGC-1β transcriptional coactivators stimulates mitochondrial respiration, at least in osteosarcoma cybrids. 3) Overexpression of PGC-1α stimulates complex IV activity. 4) Overexpression of PGC-1α/β transcriptional coactivators can stimulate respiration in oxidative phosphorylation-deficient cells. 1) In V425 cells, the Ca2 + −dependent signaling events are active for relatively longer periods, which in turn might activate the nuclear genes (including PGC-1α/β) involved in tumor invasion and metastasis. 2) Overexpression of PGC-1α/β can stimulate respiration in oxidative phosphorylation deficient cells. 3) This pathway could be explored as a therapeutic approach for the treatment of human mitochondrial diseases.
Validation of the Use of DNA Pools and Primer Extension in Association Studies of Sporadic Colorectal Cancer for Selection of Candidate SNPs Mette Gaustadnes 2006 Results were analyzed using the χ2 test with a level of significance α = 0.05. Five SNPs were found. The SNP analysis of the (*604517)3’utr96516 was not reproducible, but it was always statistically significant. The results of this article allow us to conclude that the difference between cases and controls would be statistically significant for n = 600 cases and n = 600 controls.
SIRT1/PGC1a-Dependent Increase in Oxidative Phosphorylation Supports Chemotherapy Resistance of Colon Cancer Thomas T.Vellinga 2015 1) Chemotherapy induces SIRT1 to promote oxidative energy metabolism. This gene controls mitochondrial biogenesis by deacetylation and activation of PGC1α. 2) SIRT1 and PGC1α protect colon cancer cells against chemotherapy. Colorectal tumors shift their energy metabolism when challenged with chemotherapy. Chemotherapy induces oxidative phosphorylation in colon cancer cells via the SIRT1/PGC1a axis to help them survive treatment.
AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival Kurt W. Fisher 2015 PGC1α is not detected in HCT116 cell line. 1) PGC1β and ERRα are key downstream effectors of K-Ras, KSR1, and AMPK1. 2) Both AMPK 1 and K-Ras depletion decreased the protein levels of PGC1β. 3) PGC1β and ERRα are overexpressed in colon cancer and are required for colon cancer survival both in vivo and in vitro. The aberrant expression of PGC1β and ERRα that persists in additional tumors with oncogenic Ras alleles will reveal the importance of these transcriptional regulators in creating tumor cells and promoting their survival. This may represent a new therapeutic target.
Peroxisome proliferator-activated receptor-γcoactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate Ilenia D’Errico 2011 1) Expression level of PGC1α in the intestine is higher in differentiated enterocytes than in the proliferative compartment at the bottom of the crypts, where it has only a scattered expression. 2) PGC1α Induces Mitochondrial Proliferation and Activation in Human Intestinal Cancer Cells. 3) PGC1α induces tissue-specific accumulation of reactive oxygen species and apoptosis. 4) PGC1α Stimulates Intestinal Mitochondrial Biogenesis and Respiration in vivo, and suppresses Colorectal Carcinogenesis 1) PGC1α expression levels could influence intestinal epithelial cell fate by inducing mitochondrial-related metabolic modifications that induce apoptosis. 2) PGC1α overexpression stimulates mitochondrial biogenesis, metabolic activities and accumulation of reactive oxygen species. 3) In tissues with high aerobic energy demand, PGC1α preserves reactive oxygen species‘homeostasis; In normal intestine, PGC1α cannot induce reactive oxygen species scavenging systems.
Peroxisome Proliferator-Activated Receptor Coactivator-1alpha Enhances Antiproliferative Activity of 5′-Deoxy-5-Fluorouridinein Cancer Cells through Induction of Uridine Phosphorylase Xingxing Kong 2009 1) PGC-1 Induces the Expression of UPase in Breast and Colon Cancer Cells. 2) PGC1α-Dependent Induction of UPase Gene in Cancer Cells Is Mediated by ERRα. 3) Overexpression of PGC-1 Sensitizes Cancer Cells to 5 -DFUR. 1) PGC-1αseems to be a regulator of UPase gene transcription, whose effect is mediated by ERRα. 2) PGC1α has an effect on the absence of ERRα, suggesting the involvement of other regulatory factors. 3) In tumor cells, UPase catalyzes the transformation of 5 -DFUR to 5-FU, which inhibits their proliferation. In this way, PGC1α enhances the cell’s sensitivity to the treatment.
Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARg-coactivator 1 (PGC-1) Jonas Feilchenfeldt 2004 1) RXRα expression in tumors is similar relative to normal mucosa. 2) PGC-1 expression in the tumors was significantly decreased relative to normal mucosa. 1) PPARβ/δ may repress PPARα and PPARϒ target gene expression. 2) Reduced coactivator levels ofPGC-1 are compatible with reduced transcriptional activity of PPARϒ and hence reduced tumor suppressor activity. 3) Transcriptional activity of PPARϒ may not only be decreased by mutation and increased levels of the transcriptional repressor PPARβ/δ but also by downregulation of coactivator PGC-1 of PPARϒ.