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Cervical cancer is the second most common cancer in India. The phosphatidylinositol-3 kinase (PI3K) signaling is one of the most commonly activated pathways in cancer and comprises key molecules commonly targeted in cancer therapy. This study analyzed six PI3K pathway gene mutations.We carried out targeted next-generation sequencing of six PI3K pathway genes (PIK3CA, PIK3R1, PTEN, AKT1, TSC2, and mTOR) in a total of 93 South Indian cervical cancer samples and confirmed them by sanger sequencing.The PI3K pathway gene mutations were observed in 54.8% (51/93) of the tumors and PIK3CA was the most mutated (34.4%, 32/93), followed by TSC2 (18.3%, 17/93), and PIK3R1 (14%, 13/93). The PIK3CA hotspot mutations E542K and E545K observed in this study were likely to disrupt the p110α-p85α interaction that could result in the PI3K pathway activation. We also found a few novel mutations in PIK3R1, PTEN, AKT1, TSC2, and mTOR genes while some of the tumors harbored multiple mutations in the genes of the PI3K pathway. The majority of the tumors were positive for high-risk HPV16/18 (60.7%).The high incidence of the PI3K pathway gene mutations observed in this study could be exploited for the therapeutic management of cervical cancers.

Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPCs) during aging. The Lin28b/Hmga2 pathway controls tissue development, and the postnatal downregulation of this pathway limits the self-renewal of adult vs fetal hematopoietic stem cells (HSCs). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates messenger RNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. In this study, an analysis of wild-type and Igf2bp2 knockout mice showed that Igf2bp2 regulates oxidative metabolism in HSPCs and the expression of metabolism, protein synthesis, and stemness-related genes in HSCs of young mice. Interestingly, Igf2bp2 expression and function strongly declined in aging HSCs. In young mice, Igf2bp2 deletion mimicked aging-related changes in HSCs, including changes in Igf2bp2 target gene expression and impairment of colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status had no effect on these parameters in HSCs. Unexpectedly, Igf2bp2-deficient mice exhibited an amelioration of the aging-associated increase in HSCs and myeloid-skewed differentiation. The results suggest that Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSCs, which is necessary for full HSC function during young adult age. However, Igf2bp2 gene function is lost during aging, and it appears to contribute to HSC aging in 2 ways: the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSCs, and the activity of Igf2bp2 at a young age contributes to aging-associated HSC expansion and myeloid skewing. Ministry of Education (MOE) Funding support for this article was provided by the the German Research Foundation (DFG) within the collaborative research center “PolyTarget” (to K.L.R.) and by an Ong Tiong Tat Professorship financed by Ministry of Education, Singapore (to B.O.B.). SFB1278, project ID: 316213987.

Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p

Tyrosine kinase inhibitor (TKI) is one of the effective chemo-preventive approaches against tumors that deregulate EGFR pathway. About 80% of HNSCC patients overexpress EGFR, making TKI an effective treatment against this cancer. Recently a synonymous variant rs10251977 in exon 20 of EGFR reported to act as a prognostic marker in HNSCC. Analysis of this germline variant in blood samples of oral cancer patients showed a similar frequency in cases and controls. Further, in-silico analysis showed that this polymorphism creates binding site for miR-891b in EGFR-AS1. The EGFR-AS1 expression modulates the EGFR A/D isoforms through alternative splicing. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of a few intronic polyA sites spanning around exon 15a and 15b of EGFR facilitating the skipping of exon 15b and thereby promoting the splicing of EGFR-A isoform. In addition, the presence of PTBP1 binding site in EGFR and EGFR-AS1 enhances the expression of EGFR- A isoform by preventing the premature termination. Expression profiling of EGFR-AS1 along with miR-891b level and rs10251977 polymorphism status in oral cancer patients may be useful for targeted therapy

The G0/G1 switch gene 2 (G0s2) has putative roles in cellular proliferation and fat metabolism. While activated blood mononuclear cells increase the expression of G0S2, cancer cells silence it by promoter methylation. Moreover, G0S2 was shown to act as a proapoptotic factor and recently as an inhibitor of the adipose triglyceride lipase (ATGL) in cell cuture studies. Nonetheless, the role of G0S2 in an in vivo setting remains elusive. Here I describe the characterization of a novel G0s2 knockout mouse model. G0s2 knockout mice are born at expected mendelian ratio and develop normally under normal and high fat diet feeding conditions. Liver regeneration is improved in mice with G0s2 deletion under starvation conditions. Improved cell cycle re-entry in G0s2 knockout livers after partial hepatectomy is associated with decreased triglyceride deposition and lipid droplet formation after 20h of starvation. Supporting the notion of G0S2 acting as a cell cycle inhibitor under certain conditions, over-expression of G0S2 in the hematopoietic system improves stem cell function and hematopoietic reconstitution by maintaining stem cell quiescence and inhibiting their depletion during serial transplantation. This data suggests that G0S2 has cell-cycle regulatory functions in liver and hematopoietic system possibly involving its role in modulating fat metabolism in mice starvation.

DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues., Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al. show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.