Tumor-promoting Event Research Articles

Abstract B011: BRCA2 haploinsufficiency induces P53 degradation in primary mammary epithelial cells – a crucial early event in breast tumor promotion

Abstract The presence of heterozygous germline BRCA2 mutations is associated with an increased risk of breast and ovarian cancer. In order to design effective preventative strategies, it is critical to understand early tumor promoting events that the mammary epithelial cells undergo on their way to tumorigenesis. To investigate the impact of BRCA2 heterozygosity on tumor formation, we utilized primary BRCA2mut/+ mammary epithelial cells obtained from prophylactic breast tissue of women with BRCA2 mutations. Our findings indicate that BRCA2mut/+ cells display haploinsufficiency for repairing stalled replication forks and resolving RPA32 from these sites, indicative of impaired stalled fork repair. Moreover, they exhibit defects in RAD51 recruitment to double strand break sites indicating a defective homologous recombination dependent double strand break repair efficiency. BRCA2mut/+ cells also show increased sensitivity to both replication stress and double strand break-inducing agents. Interestingly, we find that BRCA2 heterozygous cells downregulate P53 protein levels when compared to BRCA2 wild type cells, and that this downregulation is MDM2-dependent. The decreased P53 levels appear to promote the survival of BRCA2 heterozygous cells under endogenous replication stress conditions. Notably, treatment with nutlin, a P53 protein stabilizer, leads to cell death in BRCA2 heterozygous cells but not in BRCA2 wildtype cells, highlighting the sensitivity of BRCA2 heterozygous cells to endogenous P53 protein levels. Moreover, complete loss of P53 in BRCA2 heterozygous cells results in rescue of sensitivity of these cells to both replication stress and double strand break inducing agents. Furthermore, whole genome sequencing analysis of BRCA2 heterozygous cells deleted for P53 reveal DNA mutational signatures similar to those observed in BRCA2 mutant tumors, implying that loss or downregulation of P53 is an early event driving tumorigenesis in the context of BRCA2 heterozygosity. In summary, our study uncovers the significance of BRCA2 haploinsufficiency in replication stress suppression and highlights the role of P53 loss in promoting BRCA2 heterozygosity-driven cancer. These findings contribute to a better understanding of the molecular mechanisms underlying BRCA2-associated tumorigenesis and may have implications for targeted preventative therapies in the future. Citation Format: Haohui Duan, Margaret Gillis, Deboral Dillon, Judy Garber, Shailja Pathania. BRCA2 haploinsufficiency induces P53 degradation in primary mammary epithelial cells – a crucial early event in breast tumor promotion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B011.

GPCRs as targets for flavonoids in cancer cells: new options for intervention.

For a long time, the family of receptor tyrosine kinases, including epidermal growth factor receptor and insulin-like growth factor 1 receptor, was regarded as the main players stimulating cell proliferative signaling. Today, it is increasingly clear that many G protein-coupled receptors (GPCRs) are also involved in controlling the hallmarks of cancer by activating diverse intracellular signaling networks. GPCRs can therefore be considered as promising drug targets for fighting against diverse types of human malignancies. Although plant polyphenols, flavonoids, are well known for their diverse anticancer effects inhibiting the growth, proliferation, migration, and invasion of malignant cells, involvement of GPCRs in these activities has still remained largely unelucidated. Therefore, in this review article, the current knowledge about the role of GPCRs in anticancer action of structurally varied flavonoids is compiled, highlighting the ability of these natural polyphenols to modulate the expression levels of GPCRs but also suppress the action of endogenous ligands and downstream tumor-promoting events. These data show that targeting the respective GPCRs by specific flavonoids may open new perspectives in the therapeutic intervention in human malignancies.

Roles of Therapeutic Bioactive Compounds in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is due to poor prognosis and lack of availability of effective treatment. Novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells of ROS-induced tumor-promoting events. This review discusses the generation of ROS, the major signaling their modulation in therapeutics. We explore some of the major pathways involved in HCC, which include the VEGF, MAPK/ERK, mTOR, FGF, and Ser/Thr kinase pathways. In this review, we study cornerstone on natural bioactive compounds with their effect on hepatocarcinomas. Furthermore, we focus on oxidative stress and FDA-approved signaling pathway inhibitors, along with chemotherapy and radiotherapy enhancers which with early evidence of success. While more in vivo testing is required to confirm the findings presented here, our findings will aid future nonclinical, preclinical, and clinical studies with these compounds, as well as inspire medicinal chemistry scientists to conduct appropriate research on this promising natural compound and their derivatives.

Abstract B36: Tracking the path of breast tumorigenesis in BRCA1 mutant breast cancer

Abstract Women with mutations in breast cancer (BrCa) gene BRCA1 are highly predisposed to BrCa. In these families, cancer develops almost exclusively in females and often at very young ages. The molecular pathogenic steps, especially the earliest ones that drive the transition of normal mammary epithelial cells (BRCA1mut/+) to tumor cells, are largely unknown. Mouse model-based studies have not successfully addressed this question, in part because, unlike women with BRCA1 (B1) mutations, B1 heterozygous mice do not form mammary tumors any faster than the wild-type (wt) mice. A mouse model that can biologically mimic what is happening in the mammary tissue of B1 mutation carriers would be an invaluable tool to study B1 mutant BrCa. Furthermore, most of the efforts to study breast tumor-associated gene changes have been based on GWAS studies or RNA-seq based analysis of the breast tumor samples. Such studies have shown that the transcriptional network is altered in the breast tumors compared to wild-type tissue. However, whether those changes are tumor initiating, i.e., “driver” changes, or are “passenger” mutations/changes is still not clear. Given the role of B1 in suppressing replication stress (RS), a tumor-promoting event, and the increased RS observed in B1 heterozygous cells, we have established an RS-driven B1 BrCa mouse model to study the early genetic changes that drive B1 mutant cancer. We find that intraductal injections of 4-nitroquinoline-1-oxide (4NQO1, a replication stress-inducing agent) leads to breast adenocarcinoma in B1flx/wt;Trp53flx/flx,K14Cre mice on average 84 days post injections unlike B1 wt mice that do not make tumors. This is the first RS-induced BrCa model that can successfully recapitulate B1 mutant BrCa. The fast timeline of tumor formation provides significant advantage for studying tumor formation, progression, and response to therapy. Furthermore, single-cell RNA sequencing analysis of the breast adenocarcinoma and tissue collected early during injections in these mice has revealed presence of a highly proliferative “transdifferentiated population” that shares properties of both luminal and basal cells (e.g., K8+K18+) and also exists in the hyperplastic tissue. No such population was found in control PBS injected mammary fat pad of B1flx/wt;Trp53flx/flx,K14Cre mice, indicating that this population might be dependent on RS. We also find that this population is enriched very early during mammary tumorigenesis and some of the top hits include cancer stem cell markers. We have also confirmed the presence of this population by immune histochemistry-based experiments. Finally, our study provides evidence for a BrCa mouse model where basal-like tumor formation is driven by RS. We also found evidence for an early precancerous transdifferentiated population that is enriched upon RS and have identified early markers that can potentially drive breast tumorigenesis in B1 mutant BrCa. Identification of such candidate genes is critical in the design of future preventive and/or therapeutic strategies. Citation Format: Joshua Rivera, Delan Khalid, Stevenson Tran, Kemmie Kibaja, Shailja Pathania. Tracking the path of breast tumorigenesis in BRCA1 mutant breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B36.

Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer.

BackgroundAlterations in claudin expression can impair tight junction function, influence signaling pathways, and act as a tumor-promoting event in some epithelial cancers. Recently, zolbetuximab, a highly potent and tumor cell-selective therapeutic antibody against claudin 18.2, has been developed and investigated in clinical trials.MethodsWe conducted a prospective study using claudin 18.2 immunohistochemistry in 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016.ResultsClaudin 18.2 expression was evaluated in 96.3% of the patients (414/430) using immunohistochemistry. In total, 4.1% (17/414) of the patients were claudin 18.2-positive, including patients with pancreatic (16.7%, 1/6), gastric (14.1%, 12/85), biliary tract (6.3%, 1/16), genitourinary/miscellaneous (2.2%, 1/46), and colorectal (0.9%, 2/203) cancers. Twelve of 17 patients positive for claudin 18.2 had gastric cancers (GCs); this subgroup showed no statistical differences by gender, age, disease extent, primary tumor site, pathologic differentiation, human epidermal growth factor receptor 2, or Epstein-Barr virus status with or without claudin 18.2 expression. However, claudin 18.2 was more frequently positive in intestinal-type compared with diffuse-type as assessed by Lauren classification (P=0.026). There was no significant difference in overall survival (OS) between patients with and without claudin 18.2 expression (P=0.101).ConclusionsOur results add to the emerging literature about claudin 18.2 expression in various cancer types and support the need for extended clinical exploration of zolbetuximab.

Oxidative Stress-Driven Autophagy acROSs Onset and Therapeutic Outcome in Hepatocellular Carcinoma.

Reactive oxygen species- (ROS-) mediated autophagy physiologically contributes to management of cell homeostasis in response to mild oxidative stress. Cancer cells typically engage autophagy downstream of ROS signaling derived from hypoxia and starvation, which are harsh environmental conditions that need to be faced for cancer development and progression. Hepatocellular carcinoma (HCC) is a solid tumor for which several environmental risk factors, particularly viral infections and alcohol abuse, have been shown to promote carcinogenesis via augmentation of oxidative stress. In addition, ROS burst in HCC cells frequently takes place after administration of therapeutic compounds that promote apoptotic cell death or even autophagic cell death. The interplay between ROS and autophagy (i) in the disposal of dysfunctional mitochondria via mitophagy, as a tumor suppressor mechanism, or (ii) in the cell survival adaptive response elicited by chemotherapeutic interventions, as a tumor-promoting event, will be depicted in this review in relation to HCC development and progression.

Wedelolactone mitigates UVB induced oxidative stress, inflammation and early tumor promotion events in murine skin: plausible role of NFkB pathway

UVB (Ultra-violet B) radiation is one of the major etiological factors in various dermal pathology viz. dermatitis, actinic folliculitis, solar urticaria, psoriasis and cancer among many others. UVB causes toxic manifestation in tissues by inciting inflammatory and tumor promoting events. We have designed this study to assess the anti-inflammatory and anti-tumor promotion effect of Wedelolactone (WDL) a specific IKK inhibitor. Results indicate significant restoration of anti-oxidative enzymes due to WDL treatments. We also found that WDL was effective in mitigating inflammatory markers consisting of MPO (myeloperoxidase), Mast cells trafficking, Langerhans cells suppression and COX 2 expression up regulation due to UVB exposure. We also deduce that WDL presented a promising intervention in attenuating early tumor promotion events caused by UVB exposure as indicated by the results of ODC (Ornithine Decarboxylase), Thymidine assay, Vimentin and VEGF (Vascular-endothelial growth factor) expression. This study was able to provide substantial cues for the therapeutic ability of Wedelolactone against inflammatory and tumor promoting events in murine skin depicting plausible role of NFkB pathway.

075 Ephrin-A loss in cutaneous squamous cell carcinoma progression and metastasis

075 Ephrin-A loss in cutaneous squamous cell carcinoma progression and metastasis

078 Dsg2 enhances spontaneous BCC formation in Ptc1+/−mice

078 Dsg2 enhances spontaneous BCC formation in Ptc1+/−mice

Abstract A46: Transcriptome analysis on tumor and its normal cerebellar counterpart from mouse models reveals molecular mechanisms underlying evolution of SHH and Group3 medulloblastoma

Abstract Human medulloblastoma (MB) consists of four molecular subgroups. In spite of enormous effort majority of current MB mouse models are SHH subgroup, represented by Patched heterozygous mice (designated as SHH-A). GTML MB is the only published spontaneous Group3 MB mouse model (designated as G3), which was induced by expressing MycN under the regulation of GLT1 promoter. By using Sleeping Beauty transposon system we have created and published two SHH mouse models: Math1SB11/T2Onc/Ptch+/- (designated as SHH-B) and Math1SB11/T2Onc/P53mut (designated as SHH-C). To dissect the molecular mechanism of SHH and Group3 MB during tumor evolution (initiation, maintenance and maturation), we profiled transcriptomes on SHH-A, SHH-B, SHH-C and G3 MBs along with normal mouse cerebellum (CB) of different developmental stage (E15, E18, P0, P60, P95 and P122). Fetal and/or adult human CBs are routinely used as normal controls for human pediatric MBs. One major advantage of profiling mouse tumor samples over human tumor samples is the availability of age-matched normal mouse CB counterparts. This is particularly true in case of developmental diseases such as pediatric MBs. Indeed, our study showed that transcriptomes of normal mouse CB from E15, E18 and P0 (designated as EdCB, representing early developmental CB), are similar to each other but distinct from mouse CB at P60, P95 and P122 (designated as LdCB, representing late developmental CB). Importantly P60 to P120 are the ages at which most of spontaneous MBs are harvested from a tumor-bearing mouse. We therefore analyzed global gene expression level of MBs and EdCB in comparison with LdCB, the mouse MB's normal counterparts. As a developmental disease, MB is presumably initiated from a single cell or a single cell clone that is transformed at an early developmental stage of a normal CB. In fact, it is well known that a SHH MB is initiated from transformation of granule cell precursors at EGL, the external granule layer. However, it is unclear about the initiation of Group3 MB. In this study we showed that compared to a normal LdCB, a particular MB transriptome harbors four major types of abnormally expressed genes: 1. Genes not only specific to one subgroup but also shared with EdCB; representing tumor initiation events. 2. Genes specific to a subgroup only; representing subgroup-specific tumor promotion events. 3. Genes shared not only by both subgroups but also by EdCB, representing non-subgroup specific tumor maintenance events; 4. Genes shared by both subgroups only; representing non-subgroup specific late tumor maturation events. We confirmed that SHH MBs from SHH-A, B, and C are all initiated at Math1/Atoh1 expressing cells, which are further transformed by up-regulation of Olig3 and MycN among other genes. Rxrg-expressing cells are identified as Group3 MB initiating cells, which are further transformed by over-expression of Crx (Otx3) along with other genes such as Otx2, and down-regulation of cerebellum-specific Zic1 and others such as Lgi1. Both subgroups of MBs may be maintained and mature as genes associated with cell cycle, mitosis and chromosome integrity, such as KIFs, CDK1, PLK1/4, AURKA/B, CENP family and MCMs are abnormally overexpressed. Our study reveals distinct molecular mechanisms underlying tumor evolution of SHH and Group3 MBs. We propose a MB evolution model, illustrating how a normal cell at specific cell of origin can be transformed to a fully developed subgroup specific MB. Furthermore, our results demonstrate that despite the fact that they are initiated from distinct cell of origin, different subgroup of MBs do share common abnormal molecular events for tumor maintenance and maturation, suggesting that subgroup specific target therapies alone may be not as effective as their combination with therapies targeting abnormalities common to different subgroup of MBs. Citation Format: Xiaochong Wu, Adrian Dubuc, William A. Weiss, Robert J. Wechsler-Reya, Michael D. Taylor. Transcriptome analysis on tumor and its normal cerebellar counterpart from mouse models reveals molecular mechanisms underlying evolution of SHH and Group3 medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A46.

The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression.

Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

Nordihydroguiaretic acid attenuates skin tumorigenesis in Swiss albino mice with the condition of topical co-administration of an immunosuppressant

Drug and chemically-induced immunosuppression has been implicated as a confounding factor for cancer development. Management of cancer in such situation is often a challenging task. We tested the efficacy of nordihydroguiaretic acid (NDGA) against immunosuppressant tacrolimus-induced augmentation of mouse skin tumorigenesis. It was observed that topical administration of tacrolimus significantly accelerated the tumor promotion events in dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted two-stage mouse skin carcinogenesis, which were accompanied by reduced CD4+/CD8+ ratio of lymph nodes and serum IL-2 level. NDGA pre-treatment before each TPA application reduced the tumor incidence, its multiplicity and volume together with improvement in histopathological alterations and decrease in proliferating cell nuclear antigen (PCNA) labeling index (LI). However, NDGA had no significant influence on the immunosuppressive effect of tacrolimus. The present study demonstrates chemopreventive effect of NDGA in normal as well as in the condition of immunosuppression. Thus, NDGA has the potential to inhibit or delay the onset of tumor development during immunosuppressive regimen.

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.

STAT3 in hepatocellular carcinoma: new perspectives.

Chronic liver damage and inflammation are strong promoters of hepatocellular carcinoma (HCC) formation. HCC cells communicate with inflammatory and stromal cells via cytokine/chemokine signals. These heterotypic interactions inhibit immunologic anticancer activities and promote protumorigenic activities, such as angiogenesis or invasiveness. STAT3 mediates several reciprocal interactions between liver cancer cells and stromal cells and modulates preconditions of tumor formation such as chronic inflammation. Therefore, activation of STAT3 is considered as a tumor-promoting event in HCC formation. However, the oncogenic role of STAT3 in cancers has been challenged by several reports that suggest a tumor-suppressive activity. Here we discuss tumor-promoting and tumor-suppressive effects of cytokine-activated STAT3 in HCC.

Abstract B03: Loss of the Polycomb mark at bivalent promoters leads to activation of intestinal stem cell genes in colorectal cancer

Abstract During tumor formation, transcription of many genes becomes deregulated. In order to elucidate epigenetic mechanisms responsible for this phenomenon, we analyzed genome-wide patterns of several histone marks, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in human stage II colorectal cancer and matching normal tissue samples. By using liquid chromatography—mass spectrometry (LC-MS/MS), we determined that colon tumors have strongly reduced global levels of 5hmC. However, Tet-assisted bisulfite sequencing showed that site-specific loss of 5hmC in tumors is not associated with localized aberrant CpG island hypermethylation. We observed that DNA hypermethylation is generally targeted to bivalent promoters, which loose H3K27me3 and the associated genes are repressed effectively. Importantly, loss of H3K27me3 at bivalent promoters is not always coupled with gain of 5mC. Instead, H3K27me3 loss is also frequently associated with activation of intestinal stem cell markers and stem cell regulators including LGR5, SOX9, CDX1, CDX2, KLF5, and SALL4 as well as activation of many genes linked to colorectal cancer progression such as MET, CLDN1, PTGS2 (COX-2) and CCND1 (cyclin D1). Activation of these genes correlates with accumulation of the active chromatin mark H3K4me3 at their promoters. Our study demonstrates two distinct features of H3K27me3 loss in cancer. Loss of H3K27me3 at bivalent genes can be accompanied by either gain of 5mC and strong repression or by persistence or gain of H3K4me3 and gene activation. We propose that instability of H3K27me3 coupled with selection for tumor-promoting events plays a major role in colorectal cancer progression most notably by causing activation of cancer driving genes including factors involved in stem cell maintenance. Citation Format: Maria A. Hahn, Arthur X. Li, Xiwei Wu, Daniel W. Rosenberg, Gerd P. Pfeifer. Loss of the Polycomb mark at bivalent promoters leads to activation of intestinal stem cell genes in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B03.

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Pituitary adenomas in young patients: when should we consider a genetic predisposition?

. They are frequently endowed with specific, age-related endocrine morbidities owing to the impact of pituitary dysfunction on somatic growth, pubertal development and fertility. These effects may be life-long and can have a significant psychosocial impact. The need for multiple therapeutic modalities (including recurrent surgery and radiotherapy), and the risks for neuro-logical sequalae and pituitary dysfunction, increase with tumor size and aggressive-ness. Therefore, achieving an early diagno-sis of PA provides an advantage to achiev-ing a cure and a normal adult life. From this perspective, awareness of a genetic predisposition to PA is essential. Recent discoveries regarding the pathogenesis and epidemiology of PA may contribute to this effort and modify the clinical approach to young patients with PA.The pathogenesis of PA is multifactorial, generally involving a number of tumor-promoting somatic events and extracellular signals inducing cell cycle dysregulation

The tumor-promoting activity of 2-acetylaminofluorene is associated with disruption of the p53 signaling pathway and the balance between apoptosis and cell proliferation

The aromatic amine 2-acetylaminofluore (2-AAF) is a powerful complete genotoxic rat liver carcinogen that induces tumors without any additional interventions. While the tumor-initiating genotoxic activity of 2-AAF is well established, its tumor-promotion activity is far less understood. It is believed that the tumor-promoting property of 2-AAF is associated with selective enhancement of cell replication and sustained suppression of apoptosis in initiated cells. In the present study, we investigated the underlying mechanisms of tumor-promoting events induced by 2-AAF-exposure. Male Sprague–Dawley rats were fed NIH-31 diet containing 0.02% of 2-AAF for 12 and 24 weeks, and the expression pattern of genes associated with the p53-signaling pathway and microRNA genes was determined in the livers of control and 2-AAF-fed rats. The results indicate that the tumor-promoting property of 2-AAF during hepatocarcinogenesis is associated predominantly with the up-regulation of anti-apoptotic growth-related genes and down-regulation of expression of pro-apoptotic genes. This disrupts the balance between cell proliferation and apoptosis, which leads to consequential unrestricted cell proliferation, especially of initiated cells. Also, the long-term-administration of 2-AAF resulted in disruption of regulatory miR-34a-p53 feed-back loop that mediates apoptosis. This was evidenced by an increased expression of miR-34a in response to genotoxic effects of 2-AAF in the absence of p53 up-regulation, and loss of regulatory control of mir-34a on SIRT1 function. Additionally, the livers of 2-AAF-exposed rats were characterized by the substantial deregulation of expression of miR-18, miR-21, miR-182, and miR-200 family, microRNAs involved in control of apoptosis/cell proliferation and cell–cell contact pathways, two major pathways disrupted during the promotion stage of hepatocarcinogenesis.

Elevated Serum Leptin Levels: A Risk Factor for Non-Small-Cell Lung Cancer?

Objective: Leptin is intimately intertwined in the molecular pathophysiology of several cancer types; with regard to lung cancer, however, limited research has been conducted, with overall conflicting results. Methods: The present case-control study comprises 66 non-small-cell lung cancer (NSCLC) cases and 132 healthy controls matched for gender and age. Lifestyle, sociodemographic and medical history information has been obtained in addition to body mass index (BMI) measurements and weight change during the last 2 months. Serum leptin and adiponectin levels were determined following a standard protocol. Results: In multiple logistic regression analyses, elevated serum leptin emerged as a risk factor for NSCLC independent of central obesity, more pronounced after controlling for BMI and recent weight loss (odds ratio = 4.58, 95% confidence interval: 1.94–10.82). Additionally, smoking and animal foods consumption were strongly associated with the disease, whereas plant foods consumption showed a protective association. Conclusions: The observed higher serum leptin levels in NSCLC cases might be attributed to direct or indirect effects mediated by cancer- or cachexia-related cytokines. In line with the growth-promoting properties of leptin in the lung tissue documented elsewhere, increased serum leptin concentration may represent a tumor-promoting event during non-small-cell lung carcinogenesis.

RETRACTED: IL-12 Deficiency Exacerbates Inflammatory Responses in UV-Irradiated Skin and Skin Tumors

IL-12 deficiency has been shown to promote photocarcinogenesis in mice. As UVB-induced inflammation is an important tumor-promoting event in the development of skin tumors, we determined the effects of IL-12-deficiency on UVB-induced inflammatory responses in mice. For this purpose, IL-12-knockout (IL-12 KO) and their wild-type counterparts were subjected to a photocarcinogenesis protocol; skin and tumor samples were collected at the termination of the experiment, and analyzed for biomarkers of inflammation and their mediators. We found that the levels of infiltrating leukocytes, myeloperoxidase, proliferating cell-nuclear antigen (PCNA), COX-2, PGE2, and the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6 were higher in the UVB-exposed skin of IL-12 KO than in that of wild-type mice. In a short-term experiment, pretreatment of IL-12 KO mice with rIL-12 (50 ng per mouse) before each exposure to UVB increased the repair rate of UVB-induced cyclobutane pyrimidine dimers, while inhibiting UVB-induced increases in myeloperoxidase, COX-2, PGE2, PCNA, TNF-alpha, and IL-1beta in the skin as compared with non-rIL-12-treated IL-12 KO mice. Similarly, tumors of IL-12 KO mice expressed higher levels of inflammatory responses than those of wild-type mice. Together, our data suggest that IL-12 KO mice are more susceptible to both UVB-induced inflammation and photocarcinogenesis because of the deficiency in the repair of UVB-induced DNA damage.