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1.
Mol Metab ; 87: 101997, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39032642

RESUMO

OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.


Assuntos
Jejum , Lisossomos , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Masculino , Camundongos , Autofagia , Jejum/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Lisossomos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Biossíntese de Proteínas , Proteínas Ribossômicas/metabolismo , Proteínas Ribossômicas/genética
2.
Cancer Cell Int ; 24(1): 59, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321552

RESUMO

Peroxiredoxin 3 (PRDX3), a mitochondrial hydrogen peroxide scavenger, is known to be upregulated during tumorigenesis and cancer progression. In this study, we provide evidence for the first time that PRDX3 could regulate cellular signaling pathways associated with Matrix Metalloproteinase-1 (MMP-1) expression and activity in breast cancer progression. We show that shRNA-mediated gene silencing of PRDX3 inhibits cell migration and invasion in two triple-negative breast cancer cell lines. Reciprocal experiments show that PRDX3 overexpression promotes invasion and migration of the cancer cells, processes which are important in the metastatic cascade. Notably, this phenomenon may be attributed to the activation of MMP-1, which is observed to be upregulated by PRDX3 in the breast cancer cells. Moreover, immunohistochemical staining of breast cancer tissues revealed a positive correlation between PRDX3 and MMP-1 expression in both epithelial and stromal parts of the tissues. Further pathway reporter array and luciferase assay demonstrated that activation of ERK signaling is responsible for the transcriptional activation of MMP-1 in PRDX3-overexpressed cells. These findings suggest that PRDX3 could mediate cancer spread via ERK-mediated activation of MMP-1. Targeted inhibition of ERK signaling may be able to inhibit tumor metastasis in triple-negative breast cancer.

3.
Mol Cancer ; 22(1): 206, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38093346

RESUMO

BACKGROUND: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance. METHODS: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells. RESULTS: Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKß. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit. CONCLUSIONS: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.


Assuntos
Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Altruísmo , Fosfatidilinositol 3-Quinases , MicroRNAs/genética , Neoplasias da Mama/genética
4.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674861

RESUMO

Breast carcinoma is the most prevalent cancer in women globally, with complex genetic and molecular mechanisms that underlie its development and progression. Several challenges such as metastasis and drug resistance limit the prognosis of breast cancer, and hence a constant search for better treatment regimes, including novel molecular therapeutic targets is necessary. Complement component 1, q subcomponent binding protein (C1QBP), a promising molecular target, has been implicated in breast carcinogenesis. In this study, the role of C1QBP in breast cancer progression, in particular cancer cell growth, was determined in triple negative MDA-MB-231 breast cancer cells. Depletion of C1QBP decreased cell proliferation, whereas the opposite effect was observed when C1QBP was overexpressed in MDA-MB-231 cells. Furthermore, gene expression profiling and pathway analysis in C1QBP depleted cells revealed that C1QBP regulates several signaling pathways crucial for cell growth and survival. Taken together, these findings provide a deeper comprehension of the role of C1QBP in triple negative breast cancer, and could possibly pave the way for future advancement of C1QBP-targeted breast cancer therapy.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Neoplasias da Mama/metabolismo , Proteínas Mitocondriais/metabolismo , Transdução de Sinais , Proteínas de Transporte/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/genética
5.
Mol Biol Cell ; 34(3): ar13, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36598812

RESUMO

Rho GTPases regulate cell morphogenesis and motility under the tight control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the underlying mechanism(s) that coordinate their spatiotemporal activities, whether separately or together, remain unclear. We show that a prometastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under epidermal growth factor (EGF) stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, and cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 down-regulates local RhoA activity, which influences Rac1 binding to BPGAP1 and its subsequent activation by Vav1. Our results highlight the importance of BPGAP1 in recruiting Vav1 and Rac1 to promote Rac1 activation for cell motility. BPGAP1 also serves to control the timing of Rac1 activation with RhoA inactivation via its RhoGAP activity. BPGAP1, therefore, acts as a dual-function scaffold that recruits Vav1 to activate Rac1 while inactivating RhoA to synchronize both Rho and Rac signaling in cell motility. As epidermal growth factor receptor (EGFR), Vav1, RhoA, Rac1, and BPGAP1 are all associated with cancer metastasis, BPGAP1 could provide a crucial checkpoint for the EGFR-BPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.


Assuntos
Movimento Celular , Proteínas Ativadoras de GTPase , Humanos , Sequência de Aminoácidos , Receptores ErbB/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
6.
J Cachexia Sarcopenia Muscle ; 14(1): 198-213, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36398408

RESUMO

BACKGROUND: Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E-binding proteins (4EBPs). Whole-body knockout of S6K1 or muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1-mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear. METHODS: Mice with myofiber-specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1-mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt-TSC1mKO or S6K1-TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development. RESULTS: Here, we show that 4EBP1mt-TSC1mKO, but not S6K1-TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two-fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1-mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5-fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function. CONCLUSIONS: We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina , Sarcopenia , Animais , Camundongos , Modelos Animais de Doenças , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Sarcopenia/genética , Sarcopenia/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
7.
Knee Surg Sports Traumatol Arthrosc ; 31(5): 2030-2037, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36038668

RESUMO

PURPOSE: The aims of this study were (1) to develop a three-dimensional (3D) printed simulator that facilitates the simulation of surgical skills for portal placement, intra-articular identification of anatomical structures and arthroscope navigation for hip arthroscopy and (2) to concurrently examine the feasibility of using this simulator as an assessment tool to evaluate trainees' surgical competencies. METHODS: A simulator was developed using a combination of medical imaging, computer-aided design, and 3D printing. A cross-sectional study was conducted with 29 participants divided into 3 subgroups (novice, intermediate and experienced). All participants performed related skills on the simulator, and their performance was evaluated using different assessment parameters. The participants' qualitative feedback regarding the simulator was also collected. The data collated from each group of participants were subsequently compared. RESULTS: Significant differences were observed between the three subgroups of participants with regard to the total checklist score (F2,26 = 11.3), total Arthroscopic Surgical Skill Evaluation score (F2,26 = 92.1), overall final global rating scale score (F2,26 = 49), number of times the participants used fluoroscopy (F2,26 = 7.4), and task completion times (F2,26 = 23.5). The participants' performance in the simulated operation was correlated with their prior clinical experience. There was mainly positive feedback with regard to the fidelity and utility of the simulator in relation to the surgeons' prior clinical experience. CONCLUSIONS: This study demonstrated that a reliable hip arthroscopic simulator can be developed for use by orthopedic surgeons to evaluate their hip arthroscopic skills before performing actual surgical operations. LEVEL OF EVIDENCE: Level III.


Assuntos
Artroscopia , Cirurgiões , Humanos , Estudos Transversais , Competência Clínica , Simulação por Computador
8.
Nat Biomed Eng ; 7(3): 221-235, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36536254

RESUMO

Hepatobiliary magnetic resonance imaging (MRI) can inform the diagnosis of liver tumours in patients with liver cirrhosis and hepatitis. However, its clinical utility has been hampered by the lack of sensitive and specific contrast agents, partly because hepatocyte-specific nanoparticles, regardless of their surface ligands, are readily sequestered by Kupffer cells. Here we show, in rabbits, pigs and macaques, that the performance of hepatobiliary MRI can be enhanced by an ultrasmall nanoparticle composed of a manganese ferrite core (3 nm in diameter) and poly(ethylene glycol)-ethoxy-benzyl surface ligands binding to hepatocyte-specific transmembrane metal and anion transporters. The nanoparticle facilitated faster, more sensitive and higher-resolution hepatobiliary MRI than the clinically used contrast agent gadoxetate disodium, a substantial enhancement in the detection rate (92% versus 48%) of early-stage liver tumours in rabbits, and a more accurate assessment of biliary obstruction in macaques. The nanoparticle's performance and biocompatibility support the further translational development of liver-specific MRI contrast agents.


Assuntos
Neoplasias Hepáticas , Nanopartículas , Animais , Coelhos , Suínos , Meios de Contraste/metabolismo , Ligantes , Hepatócitos/metabolismo , Imageamento por Ressonância Magnética/métodos
9.
Singapore Med J ; 64(8): 493-496, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-35846408

RESUMO

Introduction: Microinvasion (Mi) is often thought to be an interim stage between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. This study aimed to investigate the potential influence of Mi on survival and assess its correlations with clinicopathological parameters, prognosis and molecular markers. Methods: The number of Mi foci in a cohort of 66 DCIS-Mi cases was assessed from haematoxylin and eosin-stained sections. Disease-free survival, clinicopathological parameters and biomarker expression were correlated with the number of Mi foci. Results: Higher numbers of Mi foci were found in larger tumours (P = 0.031). Conclusion: Greater extent of DCIS is associated with multifocal Mi.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Humanos , Feminino , Prognóstico , Intervalo Livre de Doença , Intervalo Livre de Progressão , Carcinoma Ductal de Mama/patologia , Invasividade Neoplásica
10.
ACS Nano ; 16(11): 18806-18821, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36278899

RESUMO

Labeling stem cells with magnetic nanoparticles is a promising technique for in vivo tracking and magnetic targeting of transplanted stem cells, which is critical for improving the therapeutic efficacy of cell therapy. However, conventional endocytic labeling with relatively poor labeling efficiency and a short labeling lifetime has hindered the implementation of these innovative enhancements in stem-cell-mediated regenerative medicine. Herein, we describe an advanced magnetothermal approach to label mesenchymal stem cells (MSCs) efficiently by local induction of heat-enhanced membrane permeability for magnetic resonance imaging (MRI) tracking and targeted therapy of stroke, where biocompatible γ-phase, ferrimagnetic vortex-domain iron oxide nanorings (γ-FVIOs) with superior magnetoresponsive properties were used as a tracer. This approach facilitates a safe and efficient labeling of γ-FVIOs as high as 150 pg of Fe per cell without affecting the MSCs proliferation and differentiation, which is 3.44-fold higher than that by endocytosis labeling. Such a high labeling efficiency not only enables the ultrasensitive magnetic resonance imaging (MRI) detection of sub-10 cells and long-term tracking of transplanted MSCs over 10 weeks but also endows transplanted MSCs with a magnetic manipulation ability in vivo. A proof-of-concept study using a rat stroke model showed that the labeled MSCs facilitated MRI tracking and magnetic targeting for efficient replacement therapy with a significantly reduced dosage of 5 × 104 transplanted cells. The findings in this study have demonstrated the great potential of the magnetothermal approach as an efficient labeling technique for future clinical usage.


Assuntos
Nanopartículas de Magnetita , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Acidente Vascular Cerebral , Ratos , Animais , Rastreamento de Células/métodos , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos
11.
Int J Comput Assist Radiol Surg ; 17(10): 1813-1821, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35831550

RESUMO

PURPOSE: The purpose of this study is to investigate the importance of general and specific surgical skills for hip arthroscopy from the perspective of surgeons in China. Concurrently, we intend to identify the preferred type of simulation that would facilitate competency of surgical trainees in performing arthroscopy and reinforce their preparation for carrying out the actual surgical procedure. METHODS: An online survey comprising 42 questions was developed by experts in hip arthroscopy and sent to 3 online communities whose members are arthroscopic surgeons in China. The responses collected were based on a 5-point Likert scale, with an open-ended comment section. Data were analyzed using one-way AVOVA and post hoc Tukey's test. RESULTS: A total of 159 valid responses from 66 junior specialist surgeons, 68 consultant surgeons, and 25 senior consultant surgeons (from 130 institutions in 27 out of 34 provincial administrative districts in China) were collected. Cognitive ability was identified as the overall most important attribute for hip arthroscopic trainees to possess, while skills relevant to the treatment of femoroacetabular impingement (FAI) were considered as the most important specific skills by the surgeons surveyed. In addition, simulation using cadaveric specimens was considered the most favorable method for surgeons to practice their surgical skills. CONCLUSION: In designing a training program for hip arthroscopy, it is essential to incorporate features that evaluate cognitive skills. It would be helpful for trainees to specifically practice skills that are often used in the treatment of some very common diseases of the hip joint, such as FAI. Using high-fidelity physical models for simulation to train skills of hip arthroscopy could be an ideal alternative and effective way to overcome problems arising from the lack of accessibility to cadaveric specimens.


Assuntos
Impacto Femoroacetabular , Treinamento por Simulação , Cirurgiões , Artroscopia/métodos , Cadáver , Impacto Femoroacetabular/cirurgia , Articulação do Quadril/cirurgia , Humanos
12.
Front Immunol ; 13: 865554, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432376

RESUMO

Breast cancer remains the most common malignancy among women worldwide. Although the implementation of mammography has dramatically increased the early detection rate, conventional treatments like chemotherapy, radiation therapy, and surgery, have significantly improved the prognosis for breast cancer patients. However, about a third of treated breast cancer patients are known to suffer from disease recurrences and progression to metastasis. Immunotherapy has recently gained traction due to its ability to establish long-term immune surveillance, and response for the prevention of disease recurrence and extension of patient survival. Current research findings have revealed that gold nanoparticles can enhance the safety and efficacy of cancer immunotherapy, through their unique intrinsic properties of good biocompatibility, durability, convenient surface modification, as well as enhanced permeability and retention effect. Gold nanoparticles are also able to induce innate immune responses through the process of immunogenic cell death, which can lead to the establishment of lasting adaptive immunity. As such gold nanoparticles are considered as good candidates for next generation immunotherapeutic strategies. This mini review gives an overview of gold nanoparticles and their potential applications in breast cancer immunotherapeutic strategies.


Assuntos
Neoplasias da Mama , Nanopartículas Metálicas , Neoplasias da Mama/terapia , Feminino , Ouro , Humanos , Imunoterapia , Masculino , Nanopartículas Metálicas/uso terapêutico , Recidiva Local de Neoplasia
13.
Cancers (Basel) ; 15(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36612261

RESUMO

Renal cell carcinoma (RCC) makes up the majority of kidney cancers, with a poor prognosis for metastatic RCC (mRCC). Challenges faced in the management of mRCC, include a lack of reliable prognostic markers and biomarkers for precise monitoring of disease treatment, together with the potential risk of toxicity associated with more recent therapeutic options. Glycosaminoglycans (GAGs) are a class of carbohydrates that can be categorized into four main subclasses, viz., chondroitin sulfate, hyaluronic acid, heparan sulfate and keratan sulfate. GAGs are known to be closely associated with cancer progression and modulation of metastasis by modification of the tumor microenvironment. Alterations of expression, composition and spatiotemporal distribution of GAGs in the extracellular matrix (ECM), dysregulate ECM functions and drive cancer invasion. In this review, we focus on the clinical utility of GAGs as biomarkers for mRCC (which is important for risk stratification and strategizing effective treatment protocols), as well as potential therapeutic targets that could benefit patients afflicted with advanced RCC. Besides GAG-targeted therapies that holds promise in mRCC, other potential strategies include utilizing GAGs as drug carriers and their mimetics to counter cancer progression, and enhance immunotherapy through binding and transducing signals for immune mediators.

14.
Breast Cancer Res Treat ; 191(1): 63-75, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34698969

RESUMO

PURPOSE: Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue. METHODS: The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A. RESULTS: Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence. CONCLUSION: The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.


Assuntos
Neoplasias da Mama , Cinesinas , Neoplasias da Mama/genética , Citoplasma , Feminino , Humanos , Cinesinas/genética , Recidiva Local de Neoplasia/genética , Prognóstico
15.
Cancers (Basel) ; 13(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34503296

RESUMO

Metastasis is the main cause of mortality in breast cancer patients. There is an unmet need to develop therapies that can impede metastatic spread. Precision oncology has shown great promise for the treatment of cancers, as the therapeutic approach is tailored to a specific group of patients who are likely to benefit from the treatment, rather than the traditional approach of "one size fits all". CD82, also known as KAI1, a glycoprotein belonging to the tetraspanin family and an established metastasis suppressor, could potentially be exploited to hinder metastases in breast cancer. This review explores the prospect of targeting CD82 as an innovative therapeutic approach in precision medicine for breast cancer patients, with the goal of preventing cancer progression and metastasis. Such an approach would entail the selection of a subset of breast cancer patients with low levels of CD82, and instituting an appropriate treatment scheme tailored towards restoring the levels of CD82 in this group of patients. Proposed precision treatment regimens include current modalities of treating breast cancer, in combination with either clinically approved drugs that could restore the levels of CD82, CD82 peptide mimics or non-coding RNA-based therapeutics.

17.
Mod Pathol ; 34(7): 1320-1332, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33727697

RESUMO

Breast fibroepithelial lesions are biphasic tumors which comprise the common benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). This study analyzed 262 (42%) conventional FAs, 45 (7%) cellular FAs, and 321 (51%) benign PTs contributed by the International Fibroepithelial Consortium, using a previously curated 16 gene panel. Benign PTs were found to possess a higher number of mutations, and higher rates of cancer driver gene alterations than both groups of FAs, in particular MED12, TERT promoter, RARA, FLNA, SETD2, RB1, and EGFR. Cases with MED12 mutations were also more likely to have TERT promoter, RARA, SETD2, and EGFR. There were no significant differences detected between conventional FAs and cellular FAs, except for PIK3CA and MAP3K1. TERT promoter alterations were most optimal in discriminating between FAs and benign PTs. Our study affirms the role of sequencing and key mutations that may assist in refining diagnoses of these lesions.


Assuntos
Neoplasias da Mama/genética , Fibroadenoma/genética , Tumor Filoide/genética , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Fibroadenoma/diagnóstico , Fibroadenoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Tumor Filoide/diagnóstico , Tumor Filoide/patologia
18.
Free Radic Biol Med ; 166: 128-139, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33636336

RESUMO

The liver kinase B1 (LKB1) is an important tumor suppressor and its loss-of-function mutations are observed in around 16% of non-small cell lung cancer (NSCLC) cases. One of the main functions of LKB1 is to activate AMP-activated protein kinase (AMPK) via direct phosphorylation. Under metabolic or energy stress conditions, the LKB1-AMPK axis inhibits the anabolic pathways and activates the catabolic pathways to maintain metabolic homeostasis for cell survival. In this study, we found that LKB1-mutant NSCLC cells are particularly susceptible to cell death induced by glucose starvation, but not by other forms of starvation such as amino acid starvation or serum starvation. Reconstitution of LKB1 in LKB1-mutant cells or LKB1 knockout in LKB1-wild type cells highlighted the importance of the LKB1-AMPK axis for cell survival under glucose starvation. Mechanistically, in LKB1-mutant cells, glucose starvation elicits oxidative stress, which causes AMPK protein oxidation and inactivation, and eventually cell death. Importantly, this process could be effectively reversed and rescued by 2DG (a glucose analog capable of producing NADPH, a key antioxidant), A769662 (an allosteric AMPK activator), and N-acetyl cysteine (NAC) (a ROS scavenger), indicating the presence of a vicious circle between AMPK inactivation and ROS in LKB1-mutant NSCLC cells under glucose starvation. Our study thus elucidates the critical role of redox balance in determining the susceptibility to cell death under glucose starvation in LKB1-mutant NSCLC cells. The findings from this study reveal important clues in search of novel therapeutic strategies for LKB1-mutant NSCLC by targeting glucose metabolism and redox balance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Glucose , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estresse Oxidativo/genética
19.
Breast Cancer Res Treat ; 186(3): 655-665, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33625616

RESUMO

PURPOSE: Breast cancer is the most common type of cancer affecting women worldwide. Phosphoglycerate dehydrogenase (PHGDH) is an oxidoreductase in the serine biosynthesis pathway. Although it has been reported to affect growth of various tumors, its role in breast cancer is largely unknown. This study aimed to analyze the expression of PHGDH in breast cancer tissue samples and to determine if PHGDH regulates breast cancer cell proliferation. METHODS: Tissue microarrays consisting of 305 cases of breast invasive ductal carcinoma were used for immunohistochemical evaluation of PHGDH expression. The role of PHGDH in breast cancer was investigated in vitro by knocking down its expression and determining the effect on cell proliferation and cell cycling, and in ovo by using a chorioallantoic membrane (CAM) assay. RESULTS: Immunohistochemical examination showed that PHGDH is mainly localized in the cytoplasm of breast cancer cells and significantly associated with higher cancer grade, larger tumor size, increased PCNA expression, and lymph node positivity. Analysis of the GOBO dataset of 737 patients demonstrated that increased PHGDH expression was associated with poorer overall survival. Knockdown of PHGDH expression in breast cancer cells in vitro resulted in a decrease in cell proliferation, reduction in cells entering the S phase of the cell cycle, and downregulation of various cell cycle regulatory genes. The volume of breast tumor in an in ovo CAM assay was found to be smaller when PHGDH was silenced. CONCLUSION: The findings suggest that PHGDH has a regulatory role in breast cancer cell proliferation and may be a potential prognostic marker and therapeutic target in breast cancer.


Assuntos
Neoplasias da Mama , Fosfoglicerato Desidrogenase , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Fosfoglicerato Desidrogenase/genética , Prognóstico , Serina
20.
Ecotoxicol Environ Saf ; 208: 111702, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396033

RESUMO

Cellular models exhibiting human physiological features of pseudostratified columnar epithelia, provide a more realistic approach for elucidating detailed mechanisms underlying PM2.5-induced pulmonary toxicity. In this study, we characterized the barrier and mucociliary functions of differentiated human small airway epithelial cells (SAECs), cultured at the air-liquid interface (ALI). Due to the presence of mucociliary protection, particle internalization was reduced, with a concomitant decrease in cytotoxicity in differentiated S-ALI cells, as compared to conventional submerged SAEC cultures. After 24-hour exposure to PM2.5 surrogates, 117 up-regulated genes and 156 down-regulated genes were detected in S-ALI cells, through transcriptomic analysis using the Affymetrix Clariom™ S Human Array. Transcription-level changes in >60 signaling pathways, were revealed by functional annotation of the 273 differentially expressed genes, using the PANTHER Gene List Analysis. These pathways are involved in multiple cellular processes, that include inflammation and apoptosis. Exposure to urban PM2.5 led to complex responses in airway epithelia, including a net induction of downstream pro-inflammatory and pro-apoptotic responses. Collectively, this study highlights the importance of using the more advanced ALI model rather than the undifferentiated submerged model, to avoid over-assessment of inhaled particle toxicity in human. The results of our study also suggest that reduction of ambient PM2.5 concentrations would have a protective effect on respiratory health in humans.


Assuntos
Poluentes Atmosféricos/toxicidade , Células Epiteliais/efeitos dos fármacos , Material Particulado/toxicidade , Transcriptoma/efeitos dos fármacos , Poluentes Atmosféricos/química , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Humanos , Tamanho da Partícula , Material Particulado/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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