Carcinogenesis or oncogenesis or tumorigenesis is literally the 'creation' of cancer. It is a process by which normal cells are transformed into cancer cells. It is characterized by a progression of changes at the cellular, genetic and epigenetic level that ultimately reprogram a cell to undergo uncontrolled cell division, thus forming a malignant mass.

Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Cheng et al. revealed that ammonia, released from glutamine, promotes lipogenesis via activation of Sterol regulatory element-binding proteins (SREBPs), Endoplasmic Reticulum-Bound Transcription Factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation, and suppresses tumor growth. The study characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP-Insig dissociation and SREBP-1 activation to promote tumor growth and demonstrates that SCAP is a critical sensor of glutamine, glucose, and sterol levels to precisely control lipid synthesis 1).

Increasing evidence has suggested that microRNAs (miRNAs) are critical regulators of tumorigenesis 2).

The induction of epithelial mesenchymal transition (EMT) is important for carcinogenesis and cancer progression.

Survival of patients with glioma remains poor, which is largely attributed to active carcinogenesis.

The Hippo signaling pathway plays a crucial role in suppressing tumorigenesis.

Huang et al. identified differentially expressed genes and Competing endogenous RNA (ceRNA) networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncRNAs, 1 miRNA, and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed crosstalk signaling pathways among these genes that were correlated with the circadian rhythm, tumor immune microenvironment, and cellular senescence pathways. In conclusion, the work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signaling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy 3).

Cheng C, Geng F, Li Z, Zhong Y, Wang H, Cheng X, Zhao Y, Mo X, Horbinski C, Duan W, Chakravarti A, Cheng X, Guo D. Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nat Metab. 2022 May 9. doi: 10.1038/s42255-022-00568-y. Epub ahead of print. PMID: 35534729.
Li Q, Zhou L, Wang M, Wang N, Li C, Wang J, Qi L. MicroRNA-613 impedes the proliferation and invasion of glioma cells by targeting cyclin-dependent kinase 14. Biomed Pharmacother. 2017 Dec 28;98:636-642. doi: 10.1016/j.biopha.2017.12.044. [Epub ahead of print] PubMed PMID: 29289838.
Huang Y, Gao X, Yang E, Yue K, Cao Y, Zhao B, Zhang H, Dai S, Zhang L, Luo P, Jiang X. Top-down stepwise refinement identifies coding and noncoding RNA-associated epigenetic regulatory maps in malignant glioma. J Cell Mol Med. 2022 Feb 22. doi: 10.1111/jcmm.17244. Epub ahead of print. PMID: 35194922.
  • tumorigenesis.txt
  • Last modified: 2022/05/10 11:21
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