Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by ll

Peroxiredoxins are a family of antioxidant enzymes conserved from bacteria to humans. In Saccharomyces cerevisiae, there exist five peroxiredoxins, among which Tsa2p shares striking homology with the well described Tsa1p but has not been extensively studied. Here we report on the functional characterization of yeast tsa2⌬ mutants and the comparison of TSA1 with TSA2. The tsa2⌬ and tsa1⌬ tsa2⌬ cells grew normally under aerobic conditions. However, the tsa1⌬ tsa2⌬ mutant yeast was more susceptible to oxidants than either tsa1⌬ or tsa2⌬ cells. Notably, the tsa1⌬ tsa2⌬ yeast was also hypersensitive to peroxynitrite and sodium nitroprusside. This phenotype was rescued by the expression of either the TSA1 or TSA2 gene. The demonstration of a peroxynitrite reductase activity of Tsa2p in vitro points to a pivotal role for peroxiredoxins in the protection against nitrosative stress. In yeast cells, Tsa1p and Tsa2p exhibited comparable antioxidant activity. While the basal expression level of TSA1 was significantly higher than that of TSA2, the transcription of TSA2 was stimulated more potently by various oxidants. In addition, TSA2 was activated in tsa1⌬ cells in a Yap1p-dependent manner. Taken together, our findings implicate the cooperation of Tsa1p and Tsa2p in the cellular defense against reactive oxygen and nitrogen species.Living organisms are constantly exposed to reactive oxygen species (ROS) 1 that are produced during metabolism or in response to external stimuli (1). In addition to ROS, reactive nitrogen species (RNS) have emerged as another source of oxidative and nitrosative stress (2, 3). Both ROS and RNS have been implicated in various physiological and pathological processes including metabolism, immunity, inflammation, cell signaling, transcriptional regulation, and apoptosis (1-3). The cellular defense against oxidative and nitrosative stress is important for homeostasis and survival.Antioxidant enzymes are important components of the cellular defense system against ROS and RNS. In addition to well documented antioxidant enzymes such as superoxide dismutase and catalase, a novel family of peroxidases, designated peroxiredoxins, has recently been characterized (4 -6). Peroxiredoxins are found in all organisms ranging from bacteria to humans. They are thought to be active peroxidases supported by thioredoxin and other electron donors (5, 7). The amino acid sequences around the peroxidatic center characterized by a cysteine residue are highly conserved. The oxidation of the cysteine induced the formation of a decameric structure comprising five dimers (8, 9). In a more recent study, bacterial peroxiredoxin AhpC has been shown to be peroxynitrite reductase (10), thus conferring resistance to RNS (11). It remains to be seen whether eukaryotic peroxiredoxins can generally scavenge peroxynitrite in addition to hydrogen peroxide and directly protect cells from RNS.Multiple subtypes of peroxiredoxins are often found in one species (6). Thus, there are five peroxiredoxin genes (TSA1/ cTPxI/YML026W, TSA2/cTPxII/Y...

Hepatitis C virus (HCV) is the major etiological agent of blood-borne non-A non-B hepatitis and a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. HCV core protein is a multifunctional protein with regulatory functions in cellular transcription and virus-induced transformation and pathogenesis. Here we report on the identification of a bZIP nuclear transcription protein as an HCV core cofactor for transformation. This bZIP factor, designated LZIP, activates CRE-dependent transcription and regulates cell proliferation. Loss of LZIP function in NIH 3T3 cells triggers morphological transformation and anchorage-independent growth. We show that HCV core protein aberrantly sequesters LZIP in the cytoplasm, inactivates LZIP function and potentiates cellular transformation. Our findings suggest that LZIP might serve a novel cellular tumor suppressor function that is targeted by the HCV core.

The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.

Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-B is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-B signaling to mediate aerobic glycolysis. NF-B activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-B activation and Glut-1 transcription. Interfering NF-B signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-B signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKK␤-mediated phosphorylation of TSC2 at Ser 939 . Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-B/Glut-1 represents a novel therapeutic target against NPC.IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC pathogenesis. This study provides evidence that LMP1 upregulates Glut-1 transcription to control aerobic glycolysis and tumorigenic growth of NPC cells through mTORC1/NF-B signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-B/ Glut-1 signaling axis in the treatment of EBV-infected NPC.