The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

https://www.mdpi.com/2072-6694/12/10/2819/pdf

The Warburg Effect 97 Years after Its Discovery.

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in US women The invasion–metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment Each of these processes is regulated by changes in gene expression Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs) The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete

Regulation of breast cancer metastasis signaling by miRNAs

Non-small cell lung cancer (NSCLC) remains lethal despite the development of numerous drug therapy technologies. About 85% to 90% of lung cancers are NSCLC and the 5-year survival rate is at best still below 50%. Thus, it is important to find drugable target genes for NSCLC to develop an effective therapy for NSCLC. Integrated analysis of publically available gene expression and promoter methylation patterns of two highly aggressive NSCLC cell lines generated by in vivo selection was performed. We selected eleven critical genes that may mediate metastasis using recently proposed principal component analysis based unsupervised feature extraction. The eleven selected genes were significantly related to cancer diagnosis. The tertiary protein structure of the selected genes was inferred by Full Automatic Modeling System, a profile-based protein structure inference software, to determine protein functions and to specify genes that could be potential drug targets. We identified eleven potentially critical genes that may mediate NSCLC metastasis using bioinformatic analysis of publically available data sets. These genes are potential target genes for the therapy of NSCLC. Among the eleven genes, TINAGL1 and B3GALNT1 are possible candidates for drug compounds that inhibit their gene expression.

TINAGL1 and B3GALNT1 are potential therapy target genes to suppress metastasis in non-small cell lung cancer

Most cancers rely disproportionately on glycolysis for energy even in the presence of an adequate oxygen supply, a condition known as "aerobic glycolysis," or the "Warburg effect." Pyruvate dehydrogenase E1α subunit (PDHA1) is one of the main factors for the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and has been suggested to be closely associated with tumorigenesis. Here we observed that the PDHA1 protein was reduced in hepatocellular carcinoma (HCC) specimens by immunohistochemistry and Western blot, which was significantly associated with poor overall survival. To further analyze the function of PDHA1 in cancer cells, PDHA1 was upregulated in the HCC cell lines SMMC-7721 and HepG2. The results demonstrated that overexpression of the PDHA1 gene inhibited aerobic glycolysis with lower lactate via increased PDH activity; meanwhile, mitochondrial OXPHOS was enhanced accompanied with higher ATP and lower glucose consumption. We also found that apoptosis was promoted and intrinsic pathway proteins were increased in PDHA1-overexpressing cells. Collectively, our data indicate that reduced PDHA1 protein expression is associated with the poor clinical outcome of HCC. Upregulated PDHA1 gene expression can inhibit the Warburg effect and enhance the mitochondria-mediated apoptosis pathway.

Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma.

MiR-133a Acts as an Anti-Oncogene in Hepatocellular Carcinoma by Inhibiting FOSL2 Through TGF-β/Smad3 Signaling Pathway

Lenvatinib is a long-awaited alternative to Sorafenib for first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to Lenvatinib results in tumor progression and has become a major obstacle to improving the prognosis of HCC patients. Exploring the mechanisms underlying Lenvatinib resistance is considered essential for the treatment of advanced HCC. Lenvatinib resistant HCC (LR-HCC) cells were generated and potential long non-coding RNAs (Lnc-RNAs) upregulated in LR-HCC cells were identified by RNA sequencing. The effects of upregulated Lnc-RNAs were evaluated in vitro in cell models and in vivo in experimental animals using quantitative cell viability and apoptosis assays. We found that Lnc-RNA MT1JP (MT1JP) was upregulated in LR-HCC cells and inhibited the apoptosis signaling pathway. In addition, we found that sponging of microRNA-24-3p by MT1JP released Bcl-2 like 2 (BCL2L2), an anti-apoptotic protein, thereby forming a positive-feedback loop. The role of this feedback loop was validated using rescue assays. Additionally, we found that upregulation of MT1JP and BCL2L2 impaired the sensitivity of HCC cells to Lenvatinib both vitro and vivo. Our results suggest a novel molecular feedback loop between MT1JP and apoptosis signaling in Lenvatinib sensitive HCC cells.

/pdf/mt1jp-mediated-mir-24-3p-bcl2l2-axis-promotes-lenvatinib-1ce2correc.pdf

MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. MicroRNA (miRNA), a class of noncoding single-stranded RNA molecules, is involved in regulating cancer cell proliferation, metastasis, migration, invasion, and apoptosis. We showed that the expression of miR-346 was significantly increased in HCC tissues and cell lines, compared with noncancerous controls, and was associated with poor prognosis. Overexpression of miR-346 promoted proliferation and inhibited apoptosis of SMMC-7721 cells, while knockdown of miR-346 significantly suppressed proliferation and induced apoptosis of HepG2 cells. Then we identified breast cancer metastasis suppressor 1 (BRMS1) as a direct target of miR-346 based on luciferase reporter assays. There was a negative correlation between miR-346 and BRMS1 expression at both the protein and mRNA levels. Furthermore, inhibition of BRMS1 expression reversed the tumor-suppression effects of miR-346 downregulation in HepG2 cells. These results indicate that miR-346 promotes HCC progression by regulating BRMS1 expression.

miR-346 Promotes HCC Progression by Suppressing Breast Cancer Metastasis Suppressor 1 Expression

Background and purpose Tubulointerstitial nephritis antigen-like 1 (TINAGL1) is an extracellular matrix protein that plays an important role in cell adhesion and therefore modulates cell proliferation, migration, and differentiation. In addition, it is frequently upregulated in highly metastatic tumors. The aim of our study was to determine the role of TINAGL1 in the progression and metastasis of hepatocellular carcinoma (HCC). Materials and methods TINAGL1 mRNA levels were analyzed in HCC and adjacent non-tumorous samples by reverse transcription polymerase chain reaction (RT-PCR). Human HCC cell lines were transfected with lentiviral plasmids expressing either si-TINAGL1 or TINAGL1 and subjected to CCK-8, colony forming, transwell migration, Annexin V/propidium iodide, and 5-ethynyl-2'-deoxyuridine uptake assays. Suitably transfected HCC cells were injected into athymic nude mice to establish xenograft tumors that were imaged and measured on a weekly basis. Mediators of the TGF-β signaling pathway were analyzed by Western blot. Results TINAGL1 was upregulated in human HCC tissues and associated with poor prognosis. TINAGL1 knockdown suppressed HCC cell growth, proliferation, and migration and induced apoptosis in HCC cells, whereas TINAGL1 overexpression had opposite effects. In addition, inhibition of TINAGL1 retarded xenograft tumor growth in a nude mouse model. Mechanistically, TINAGL1 activated the TGF-β signaling pathway and increased VEGF secretion. Conclusion TINAGL1 promotes hepatocellular carcinogenesis and metastasis via the TGF-β/Smad3/VEGF axis and is a potential new biomarker of HCC.

/pdf/tinagl1-promotes-hepatocellular-carcinogenesis-through-the-wpza2m2ftw.pdf

Lu Sun

Papers

Overexpression of Pyruvate Dehydrogenase E1α Subunit Inhibits Warburg Effect and Induces Cell Apoptosis Through Mitochondria-Mediated Pathway in Hepatocellular Carcinoma.

MiR-133a Acts as an Anti-Oncogene in Hepatocellular Carcinoma by Inhibiting FOSL2 Through TGF-β/Smad3 Signaling Pathway

MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis

miR-346 Promotes HCC Progression by Suppressing Breast Cancer Metastasis Suppressor 1 Expression

TINAGL1 promotes hepatocellular carcinogenesis through the activation of TGF-β signaling-medicated VEGF expression.