-
Molecular Therapy Oncolytics Dec 2021Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory and fatal human malignancies. Leucine-rich repeat neuronal protein-1 (LRRN1) plays a crucial role...
Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory and fatal human malignancies. Leucine-rich repeat neuronal protein-1 (LRRN1) plays a crucial role in the development of the nervous system. However, the clinical implications and biological functions of LRRN1 in PDAC remain unclear. We found that LRRN1 expression was upregulated in PDAC tissues compared with paracancerous tissues and normal pancreatic tissues through the different public databases, tissue microarray-based immunohistochemistry, and dimethylbenzanthracene-induced PDAC murine model. The expression level of LRRN1 was closely related to the overall survival and disease-free survival of PDAC patients. Cox multivariate analysis indicated that LRRN1 was an independent adverse prognostic factor. The small hairpin RNA (shRNA)-mediated LRRN1 knockdown remarkably restrained the proliferative, migratory, and invasive capacities, as well as promoted cell apoptosis and increased G0/G1 arrest in PDAC cells. The xenograft murine subcutaneous bearing model and metastasis model verified that silencing of LRRN1 effectively dampened tumor growth and metastasis . Specifically, LRRN1 exerted its biological functions through the HIF-1α/Notch signaling pathway, and LRRN1 knockdown could dampen Jagged 1-mediated Notch pathway activation. Therefore, LRRN1 could serve as the potential therapeutic or prognostic target for PDAC.
PubMed: 34632050
DOI: 10.1016/j.omto.2021.08.012 -
The Journal of Investigative Dermatology Feb 2021Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium...
Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Carcinoma, Squamous Cell; Complement Activation; Complement C3; Complement C5; Complement Membrane Attack Complex; Disease Models, Animal; Disease Progression; Humans; Mice; Mice, Knockout; Mice, Transgenic; Neoplasms, Experimental; Receptor, Anaphylatoxin C5a; Receptors, Complement; Signal Transduction; Skin; Skin Neoplasms; Tumor Escape
PubMed: 32682912
DOI: 10.1016/j.jid.2020.06.025 -
Carcinogenesis Feb 2021More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from...
More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.
Topics: 14-3-3 Proteins; 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Apoptosis; Carcinogens; Carcinoma, Squamous Cell; Cell Line, Tumor; Cytoplasm; Female; Humans; Keratinocytes; Male; Mice; Mice, Knockout; Neoplasms, Experimental; Protein Multimerization; Skin Neoplasms; Tetradecanoylphorbol Acetate; Xenograft Model Antitumor Assays; cdc25 Phosphatases
PubMed: 32816038
DOI: 10.1093/carcin/bgaa091 -
Expert Opinion on Therapeutic Targets Feb 2020: The purpose of the present study was to examine the chemopreventive effect of stampidine, an aryl phosphate derivative of stavudine, in side by side comparison with... (Comparative Study)
Comparative Study
: The purpose of the present study was to examine the chemopreventive effect of stampidine, an aryl phosphate derivative of stavudine, in side by side comparison with the standard anti-breast cancer drug paclitaxel in the well-established 7,12-dimethylbenz(a)anthracene (DMBA)-induced murine breast cancer model.: Groups of 20 female mice were challenged with the DMBA. DMBA-challenged mice were assigned to various chemoprevention treatments, including stampidine, paclitaxel, and stampidine plus paclitaxel according to the same treatment schedules for 25 weeks.: Stampidine resulted in substantially reduced numbers of tumors, tumor weight as well as tumor size in DMBA-treated mice. Stampidine was as effective as paclitaxel in the model and their combination exhibited greater chemopreventive activity, as measured by reduced tumor incidence and improved tumor-free survival as well as overall survival of DMBA-treated mice. The length of time for the initial tumor to appear in DMBA-challenged mice treated with stampidine was longer than that of mice treated DMBA-challenged control mice. Tumors from mice treated with stampidine or stampidine plus paclitaxel displayed unique changes of a signature protein cassette comprised BRCA1, p21, Bax, and Bcl-2.: Stampidine has potent chemopreventive activity and is as effective as the standard chemotherapy drug paclitaxel in the chemical carcinogenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Breast Neoplasms; Dideoxynucleotides; Disease Models, Animal; Disease-Free Survival; Female; Mice; Mice, Inbred BALB C; Paclitaxel; Stavudine; Survival Rate; Thymidine Monophosphate; Time Factors
PubMed: 32005098
DOI: 10.1080/14728222.2020.1724961 -
The Journal of Investigative Dermatology Apr 2021Integrin α3β1 plays a crucial role in tumor formation in the two-stage chemical carcinogenesis model (DMBA and TPA treatment). However, the mechanisms whereby the...
Integrin α3β1 plays a crucial role in tumor formation in the two-stage chemical carcinogenesis model (DMBA and TPA treatment). However, the mechanisms whereby the expression of α3β1 influences key oncogenic drivers of this established model are not known yet. Using an in vivo mouse model with epidermal deletion of α3β1 and in vitro Matrigel cultures of transformed keratinocytes, we demonstrate the central role of α3β1 in promoting the activation of several protumorigenic signaling pathways during the initiation of DMBA/TPA‒driven tumorigenesis. In transformed keratinocytes, α3β1-mediated focal adhesion kinase/Src activation leads to in vitro growth of spheroids and to strong Akt and STAT 3 activation when the α3β1-binding partner tetraspanin CD151 is present to stabilize cell‒cell adhesion and promote Smad2 phosphorylation. Remarkably, α3β1 and CD151 can support Akt and STAT 3 activity independently of α3β1 ligation by laminin-332 and as such control the essential survival signals required for suprabasal keratin-10 expression during keratinocyte differentiation. These data demonstrate that α3β1 together with CD151 regulate the signaling pathways that control the survival of differentiating keratinocytes and provide a mechanistic understanding of the essential role of α3β1 in early stages of skin cancer development.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Epidermis; Humans; Integrin alpha3beta1; Keratinocytes; Mice; Neoplasms, Experimental; Signal Transduction; Skin Neoplasms; Spheroids, Cellular; Tetradecanoylphorbol Acetate; Tetraspanin 24; Kalinin
PubMed: 32805217
DOI: 10.1016/j.jid.2020.07.024 -
Proceedings of the National Academy of... Mar 2021High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown...
High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Active Transport, Cell Nucleus; Animals; Carcinogenesis; Carcinoma; Cell Nucleus; Cell Survival; DNA Breaks, Double-Stranded; DNA Repair; Female; Gene Knockout Techniques; HeLa Cells; Humans; Intravital Microscopy; Keratin-17; Keratinocytes; Keratins; Male; Mice, Knockout; Neoplasms, Experimental; Time-Lapse Imaging; Mice
PubMed: 33762306
DOI: 10.1073/pnas.2020150118 -
Pharmaceutics Jan 2024The study aimed to evaluate the antitumor and toxicogenetic effects of liposomal nanoformulations containing citrinin in animal breast carcinoma induced by...
The study aimed to evaluate the antitumor and toxicogenetic effects of liposomal nanoformulations containing citrinin in animal breast carcinoma induced by 7,12-dimethylbenzanthracene (DMBA). virgin females were divided into six groups treated with (1) olive oil (10 mL/kg); (2) 7,12-DMBA (6 mg/kg); (3) citrinin, CIT (2 mg/kg), (4) cyclophosphamide, CPA (25 mg/kg), (5) liposomal citrinin, LP-CIT (2 μg/kg), and (6) LP-CIT (6 µg/kg). Metabolic, behavioral, hematological, biochemical, histopathological, and toxicogenetic tests were performed. DMBA and cyclophosphamide induced behavioral changes, not observed for free and liposomal citrinin. No hematological or biochemical changes were observed for LP-CIT. However, free citrinin reduced monocytes and caused hepatotoxicity. During treatment, significant differences were observed regarding the weight of the right and left breasts treated with DMBA compared to negative controls. Treatment with CPA, CIT, and LP-CIT reduced the weight of both breasts, with better results for liposomal citrinin. Furthermore, CPA, CIT, and LP-CIT presented genotoxic effects for tumor, blood, bone marrow, and liver cells, although less DNA damage was observed for LP-CIT compared to CIT and CPA. Healthy cell damage induced by LP-CIT was repaired during treatment, unlike CPA, which caused clastogenic effects. Thus, LP-CIT showed advantages for its use as a model of nanosystems for antitumor studies.
PubMed: 38399235
DOI: 10.3390/pharmaceutics16020174 -
International Journal of Molecular... Apr 2023Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system,...
Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2 mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2 developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2 mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity.
Topics: Animals; Mice; 9,10-Dimethyl-1,2-benzanthracene; Carcinogenesis; Carcinogens; Papilloma; Receptors, Cannabinoid; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tumor Microenvironment
PubMed: 37175480
DOI: 10.3390/ijms24097773 -
Biomedicine & Pharmacotherapy =... Nov 2022Breast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study...
BACKGROUND
Breast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study was designed to investigate the anti-cancer effect of Canagliflozin (CNG) in an experimental model of DMBA-induced mammary carcinoma in female rats.
METHODS
18 female rats were divided into three experimental groups: Normal control, DMBA control, DMBA+ CNG treated group. DMBA (7.5 mg/kg) was injected subcutaneously in the mammary cells twice weekly for 4 weeks and CNG (10 mg/kg) was orally administered daily for an additional 3 weeks while DMBA control rats only received the vehicle for 3 weeks. Tumors' weight and volume were measured, BRCA-1 and TAC were quantified in serum samples, mTOR, caspase-1, NFκB, IL-1β, NLRP3, GSDMD and MDA were quantified in tumors' homogenates.
RESULTS
CNG treatment increased the BRCA-1 expression, suppressed mTOR inflammatory pathway, attenuated tumor inflammatory mediators; NLRP3, GSDMD, NFκB, IL-1β, suppressed the oxidative stress and inhibited tumor expression of the proliferation biomarker; Ki67.
CONCLUSION
CNG modulated mTOR-mediated signaling pathway and attenuated pyroptotic, inflammatory pathways, suppressed oxidative stress and eventually inhibited DMBA-induced mammary carcinoma proliferation.
Topics: Rats; Female; Animals; 9,10-Dimethyl-1,2-benzanthracene; Ki-67 Antigen; Canagliflozin; Mammary Neoplasms, Experimental; Rats, Sprague-Dawley; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Caspase 1; Carcinoma; TOR Serine-Threonine Kinases; Inflammation Mediators
PubMed: 36115110
DOI: 10.1016/j.biopha.2022.113675 -
Nature Communications Jul 2020Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers...
Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HRHER2 BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR BC.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Breast Neoplasms; Carcinogenesis; Disease Progression; Female; Humans; Immunotherapy; Interferon Type I; Mammary Neoplasms, Experimental; Medroxyprogesterone Acetate; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Niacinamide; Receptor, ErbB-2; Survival Analysis
PubMed: 32732875
DOI: 10.1038/s41467-020-17644-0