Interleukin-33-Enhanced CXCR4 Signaling Circuit Mediated by Carcinoma-Associated Fibroblasts Promotes Invasiveness of Head and Neck Cancer

Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients.

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Vitamin D and Ovarian Cancer: Systematic Review of the Literature with a Focus on Molecular Mechanisms

Cells ◽

10.3390/cells9020335 ◽

2020 ◽

Vol 9 (2) ◽

pp. 335 ◽

Cited By ~ 5

Author(s):

Andraž Dovnik ◽

Nina Fokter Dovnik

Keyword(s):

Systematic Review ◽

Ovarian Cancer ◽

Vitamin D ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Vitamin D Supplementation ◽

Review Of The Literature ◽

Epidemiologic Evidence ◽

Vitamin D Levels

Vitamin D is a lipid soluble vitamin involved primarily in calcium metabolism. Epidemiologic evidence indicates that lower circulating vitamin D levels are associated with a higher risk of ovarian cancer and that vitamin D supplementation is associated with decreased cancer mortality. A vast amount of research exists on the possible molecular mechanisms through which vitamin D affects cancer cell proliferation, cancer progression, angiogenesis, and inflammation. We conducted a systematic review of the literature on the effects of vitamin D on ovarian cancer cell.

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Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

Biomolecules ◽

10.3390/biom9110735 ◽

2019 ◽

Vol 9 (11) ◽

pp. 735 ◽

Cited By ~ 79

Author(s):

Vaishali Aggarwal ◽

Hardeep Tuli ◽

Ayşegül Varol ◽

Falak Thakral ◽

Mukerrem Yerer ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Protein Kinase ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Reactive Oxygen ◽

Mitogen Activated Protein Kinase ◽

Oxygen Species ◽

Mitogen Activated Protein ◽

High Concentrations

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

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Multifaced roles of PLAC8 in cancer

Biomarker Research ◽

10.1186/s40364-021-00329-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Misha Mao ◽

Yifan Cheng ◽

Jingjing Yang ◽

Yongxia Chen ◽

Ling Xu ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Molecular Function ◽

Cancer Cell Growth ◽

The Impact ◽

Functional Output

AbstractThe role of PLAC8 in tumorigenesis has been gradually elucidated with the development of research. Although there are common molecular mechanisms that enforce cell growth, the impact of PLAC8 is varied and can, in some instances, have opposite effects on tumorigenesis. To systematically understand the role of PLAC8 in tumors, the molecular functions of PLAC8 in cancer will be discussed by focusing on how PLAC8 impacts tumorigenesis when it arises within tumor cells and how these roles can change in different stages of cancer progression with the ultimate goal of suppressing PLAC8-relevant cancer behavior and related pathologies. In addition, we highlight the diversity of PLAC8 in different tumors and its functional output beyond cancer cell growth. The comprehension of PLAC8’s molecular function might provide new target and lead to the development of novel anticancer therapies.

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Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽

10.3390/cells8020129 ◽

2019 ◽

Vol 8 (2) ◽

pp. 129 ◽

Cited By ~ 9

Author(s):

Sahib Zada ◽

Jin Hwang ◽

Mahmoud Ahmed ◽

Trang Lai ◽

Trang Pham ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Nuclear Translocation ◽

Degradation Process ◽

Mesenchymal Transition ◽

Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

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Extracellular Vesicles Long Non-Coding RNA AGAP2-AS1 Contributes to Cervical Cancer Cell Proliferation Through Regulating the miR-3064-5p/SIRT1 Axis

Frontiers in Oncology ◽

10.3389/fonc.2021.684477 ◽

2021 ◽

Vol 11 ◽

Author(s):

Min Li ◽

Jing Wang ◽

Hongli Ma ◽

Li Gao ◽

Kunxiang Zhao ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cervical Cancer Cell ◽

Cancer Cell Proliferation ◽

Cervical Cancer Cells

Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth in vivo. Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation in vitro. Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.

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Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.638710 ◽

2021 ◽

Vol 9 ◽

Author(s):

Man Wang ◽

Xinzhe Chen ◽

Yuan Zhang

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Effector Proteins ◽

Biological Functions ◽

Cancer Cell Growth ◽

Cancer Pathogenesis

Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

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Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications

Diagnostics ◽

10.3390/diagnostics10080563 ◽

2020 ◽

Vol 10 (8) ◽

pp. 563

Author(s):

David Kalfert ◽

Marie Ludvikova ◽

Martin Pesta ◽

Jaroslav Ludvik ◽

Lucie Dostalova ◽

...

Keyword(s):

Thyroid Cancer ◽

Head And Neck ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Current Knowledge ◽

Human Cancer ◽

Squamous Carcinoma ◽

Transcriptional Level ◽

Mesenchymal Transition

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology.

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mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms19103267 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3267 ◽

Cited By ~ 16

Author(s):

Mio Harachi ◽

Kenta Masui ◽

Yukinori Okamura ◽

Ryota Tsukui ◽

Paul Mischel ◽

...

Keyword(s):

Amino Acid ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Cancer Cell Survival

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.

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An exploration of the role of exercise in modulating breast cancer progression in vitro (a systematic review and meta-analysis)

AJP Cell Physiology ◽

10.1152/ajpcell.00461.2020 ◽

2020 ◽

Author(s):

Marie-Juliet Brown ◽

Mhairi A. Morris ◽

Elizabeth C. Akam

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Future Research ◽

Exercise Interventions

Background: Breast cancer is the most prevalent cancer in women worldwide. In the UK, approximately 5% of all breast cancers are already metastatic at the time of diagnosis. An abundance of literature shows exercise can have beneficial effects on the outcome and prognosis of breast cancer patients, yet the molecular mechanisms remain poorly understood. There are several in vitro models that aim to recapitulate the response of breast cancer to exercise in vivo: this systematic review and meta-analysis summarises the existing literature. Methods: The following search terms were used to conduct a systematic literature search using a collection of databases (last search performed May 2020): 'in vitro' and 'exercise' and 'breast cancer'. Only studies that investigated the effects of exercise on breast cancer in vitro were included. Standardised mean differences (SMD) were calculated to determine pooled effect sizes. Results: This meta-analysis has successfully demonstrated that various identified exercise interventions on breast cancer cells in vitro significantly reduced breast cancer cell viability, proliferation, and tumourigenic potential (SMD: -1.76, p = 0.004, SMD: -2.85, p = 0.003 and SMD: -3.15, p = 0.0008, respectively). A clear direction of effect was found with exercise on breast cancer cell migration in vitro, however this effect was not significant (SMD: -0.62, p = 0.317). Conclusion: To our knowledge, this is the first meta-analysis and systematic review investigating and summarising literature on exercise and breast cancer in vitro, highlighting models used and priority areas for future research focus.

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Knockdown of Mgat5 inhibits CD133+ human pulmonary adenocarcinoma cell growth in vitro and in vivo

Clinical & Investigative Medicine ◽

10.25011/cim.v34i3.15188 ◽

2011 ◽

Vol 34 (3) ◽

pp. 155 ◽

Cited By ~ 9

Author(s):

Xuefeng Zhou ◽

Haidan Chen ◽

Qilong Wang ◽

Li Zhang ◽

Jinping Zhao

Keyword(s):

Cell Growth ◽

Western Blot ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Pulmonary Adenocarcinoma ◽

Cancer Cell Growth ◽

Adenocarcinoma Cells

Purpose: In spite of many therapeutic advances, the prognosis of lung cancer remains poor. Therefore, understanding the molecular mechanisms underlying cancer progression, invasion and metastasis is needed. Accumulating evidence indicate that N-acetylglucosaminyltransferase V (Mgat5 or GnT-V) is involved in cancer develpement. The purpose of this study was to characterize the expression and function of Mgat5 in CD133+ pulmonary adenocarcinoma cells. Methods: CD133+ pulmonary adenocarcinoma cells were separated by magnetic activated cell sorting (MACS) from excised pulmonary adenocarcinoma specimens from 10 patients. Expression of Mgat5 in CD133+ cells was detected by fluorescent quantitative RT-PCR (FQRT-PCR) and Western blot. Subsequently, CD133+ cells were transfected with specific siRNA of Mgat5 to evaluate the effects of Mgat5 inhibition on cancer cell growth in vivo and in vitro. Results: Expression of Mgat5 was 1.2-fold and 1.4-fold higher in CD133+cells than in CD133– cells detected by FQRT-PCR and Western Blot, respectively (p < 0.05). The L-PHA binding assay also showed higher reactivity in CD133+ cells than in CD133- cells. In addition, Mgat5-specific siRNA efficiently knocked down the expression of Mgat5 in CD133+ cells. Interestingly, downregulation of Mgat5 resulted in significant inhibition of cancer cell growth in vitro and in vivo. Conclusion: Mgat5 is expressed at a relatively high level in CD133+ lung adenocarcinoma cells, and knockdown of Mgat5 in CD133+ cells inhibits cancer cell growth both in vitro and in vivo. These findings suggest Mgat5 may play an important role during oncogenesis, identifying a potential therapeutic target for pulmonary adenocarcinoma.

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