scholarly journals NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Tsuyoshi Waku ◽  
Nanami Nakamura ◽  
Misaki Koji ◽  
Hidenori Watanabe ◽  
Hiroki Katoh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Rectal Adenocarcinoma ◽  
26S Proteasome ◽  
Cancer Development ◽  
20S Proteasome ◽  
Cancer Cell Growth ◽  
Protein Levels ◽  
Cancer Tissues

ABSTRACT Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap ’n’ collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins.

scholarly journals MicroRNA-154 Inhibits the Growth and Invasion of Gastric Cancer Cells by Targeting DIXDC1/WNT Signaling

2018 ◽  
Vol 26 (6) ◽  
pp. 847-856 ◽  
Author(s):  
Jifu Song ◽  
Zhibin Guan ◽  
Maojiang Li ◽  
Sha Sha ◽  
Chao Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Inverse Correlation ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Gastric Cancer Cells ◽  
Cancer Cell Growth ◽  
Cancer Tissues

MicroRNAs (miRNAs) have emerged as pivotal regulators of the development and progression of gastric cancer. Studies have shown that miR-154 is a novel cancer-associated miRNA involved in various cancers. However, the role of miR-154 in gastric cancer remains unknown. Here we aimed to investigate the biological function and the potential molecular mechanism of miR-154 in gastric cancer. We found that miR-154 was significantly downregulated in gastric cancer tissues and cell lines. The overexpression of miR-154 significantly repressed the growth and invasion of gastric cancer cells. Bioinformatics analysis and Dual-Luciferase Reporter Assay data showed that miR-154 directly targeted the 3′-untranslated region of Dishevelled‐Axin domain containing 1 (DIXDC1). Real-time quantitative polymerase chain reaction and Western blot analyses showed that miR-154 overexpression inhibited DIXDC1 expression. An inverse correlation of miR-154 and DIXDC1 was also demonstrated in gastric cancer specimens. Overexpression of miR-154 also significantly suppressed the activation of WNT signaling. Moreover, restoration of DIXDC1 expression significantly reversed the inhibitory effect of miR-154 overexpression on the cell proliferation, invasion, and WNT signaling in gastric cancer cells. Overall, these results suggest that miR-154 inhibits gastric cancer cell growth and invasion by targeting DIXDC1 and could serve as a potential therapeutic target for the treatment of gastric cancer.

Inhibitor or promoter? The performance of polysaccharides from Ganoderma lucidum on human tumor cells with different p53 statuses

2016 ◽  
Vol 7 (4) ◽  
pp. 1872-1875 ◽  
Author(s):  
Jue Zhang ◽  
Jun-ming Chen ◽  
Xiao-xia Wang ◽  
Yong-mei Xia ◽  
Steve W. Cui ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Ganoderma Lucidum ◽  
Human Tumor ◽  
Tumor Suppressor Protein ◽  
Human Tumor Cells ◽  
Cancer Cell Growth ◽  
Tumor Suppressor Protein P53

GLPs inhibit cancer cell growth when the tumor suppressor protein p53 is functional but often stimulate cancer cells when p53 is absent.

MiR-509-3-5p-NONHSAT112228.2 Axis Regulates p21 and Suppresses Proliferation and Migration of Lung Cancer Cells

2020 ◽  
Vol 20 (10) ◽  
pp. 835-846 ◽  
Author(s):  
Jing-Jing Liang ◽  
Jun-Yi Wang ◽  
Tong-Jia Zhang ◽  
Guo-Shun An ◽  
Ju-Hua Ni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Lung Cancer Cells ◽  
Cancer Cell Growth ◽  
Report Analysis ◽  
Gene Overlapping ◽  
And Migration ◽  
Cancer Tissues ◽  
Proliferation And Migration

Background: Although the involvement of individual microRNA and lncRNA in the regulation of p21 expression has largely been evidenced, less is known about the roles of functional interactions between miRNAs and lncRNAs in p21 expression. Our previous work demonstrated that miR-509- 3-5p could block cancer cell growth. Methods: To gain an insight into the role of miR-509-3-5p in the regulation of p21 expression, we performed in silico prediction and showed that miR-509-3-5p might target the NONHSAT112228.2, a sense-overlapping lncRNA transcribed by a non-code gene overlapping with p21 gene. Mutation and luciferase report analysis suggested that miR-509-3-5p could target NONHSAT112228.2, thereby blocking its expression. Consistently, NONHSAT112228.2 expression was inversely correlated with both miR-509-3-5p and p21 expression in cancer cells. Ectopic expression of miR-509-3-5p and knockdown of NONHSAT112228.2 both promoted proliferation and migration of cancer cells. Results: Interestingly, high-expression of NONHSAT112228.2 accompanied by low-expression of p21 was observed in lung cancer tissues and associated with lower overall survival. Conclusion: Taken together, our study found a new regulatory pathway of p21, in which MiR-509-3-5p functionally interacts with NONHSAT112228.2 to release p21 expression. MiR-509-3-5p— NONHSAT112228.2 regulatory axis can inhibit the proliferation and migration of lung cancer cells.

scholarly journals Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 218 ◽  
Author(s):  
M. Manirujjaman ◽  
Iwata Ozaki ◽  
Yuzo Murata ◽  
Jing Guo ◽  
Jinghe Xia ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Proteasome Inhibitor ◽  
Transcriptional Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Functions ◽  
Protein Levels ◽  
Sequestosome 1 ◽  
Huh7 Cells ◽  
Programmed Cell Death 4 ◽  
Pdcd4 Protein

PDCD4 (programmed cell death 4) is a tumor suppressor that plays a crucial role in multiple cellular functions, such as the control of protein synthesis and transcriptional control of some genes, the inhibition of cancer invasion and metastasis. The expression of this protein is controlled by synthesis, such as via transcription and translation, and degradation by the ubiquitin-proteasome system. The mitogens, known as tumor promotors, EGF (epidermal growth factor) and TPA (12-O-tetradecanoylphorbol-13-acetate) stimulate the degradation of PDCD4 protein. However, the whole picture of PDCD4 degradation mechanisms is still unclear, we therefore investigated the relationship between PDCD4 and autophagy. The proteasome inhibitor MG132 and the autophagy inhibitor bafilomycin A1 were found to upregulate the PDCD4 levels. PDCD4 protein levels increased synergistically in the presence of both inhibitors. Knockdown of p62/SQSTM1 (sequestosome-1), a polyubiquitin binding partner, also upregulated the PDCD4 levels. P62 and LC3 (microtubule-associated protein 1A/1B-light chain 3)-II were co-immunoprecipitated by an anti-PDCD4 antibody. Colocalization particles of PDCD4, p62 and the autophagosome marker LC3 were observed and the colocalization areas increased in the presence of autophagy and/or proteasome inhibitor(s) in Huh7 cells. In ATG (autophagy related) 5-deficient Huh7 cells in which autophagy was impaired, the PDCD4 levels were increased at the basal levels and upregulated in the presence of autophagy inhibitors. Based on the above findings, we concluded that after phosphorylation in the degron and ubiquitination, PDCD4 is degraded by both the proteasome and autophagy systems.

An oral second-generation proteasome inhibitor oprozomib significantly inhibits lung cancer in a p53 independent manner in vitro

2019 ◽  
Vol 51 (10) ◽  
pp. 1034-1040 ◽  
Author(s):  
Hongge Zhu ◽  
Tianhai Wang ◽  
Zhou Xin ◽  
Yiyi Zhan ◽  
Guoming Gu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Proteasome Inhibitor ◽  
Second Generation ◽  
26S Proteasome ◽  
Lung Cancer Cells ◽  
Independent Manner ◽  
P53 Expression

Abstract The destruction of proteins via the ubiquitin–proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival and are promising anticancer agents. Oprozomib (OPZ), an oral second-generation proteasome inhibitor, has been shown to inhibit the growth of several cancers in preclinical and clinical trials, including multiple myeloma and head and neck cancers, but its effects on lung cancer has not yet been determined. In this study, we evaluated the inhibitory effects of OPZ on lung cancer cell lines in vitro. The results showed that OPZ significantly suppressed cell proliferation and strongly induced apoptosis in both tested lung cancer cells independent of p53 expression. OPZ was able to cause obvious caspase 3 and PARP cleavages and stabilize p53 and its transcriptional targets p21, PUMA, and Noxa. Moreover, OPZ was capable of sensitizing lung cancer cells to the conventional chemotherapeutic drug cisplatin. Our study provides preclinical data and sheds light on the potential applications of proteasome inhibitor OPZ in lung cancer treatment.

scholarly journals TNFAIP3 Suppresses Lung Cancer Progression via Regulating Cell Proliferation and Apoptosis

2020 ◽  
Author(s):  
Han Chen ◽  
Jie Gao ◽  
Yongsheng Yu ◽  
Qian Zhou ◽  
Shan yongqi
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Colony Formation ◽  
The Cancer Genome Atlas ◽  
Lung Cancer Cells ◽  
Protein Levels ◽  
Cancer Tissues

Abstract Background: The ubiquitin-editing enzyme TNF inducible protein 3 (TNFAIP3) is a crucial regulator of inflammation and immunity. It is also involved in tumorigenesis of various cancers such as lymphomas, colorectal tumors and breast cancer. In this study, we aimed to explore the role and regulatory mechanism of TNFAIP3 in lung cancer. Methods: The expression of TNFAIP3 was determined in the Cancer Genome Atlas (TCGA) database. The levels of TNFAIP3 in lung cancer tissues was determined by immunohistochemistry (IHC) assay. TNFAIP3 knockdown and overexpression were performed, followed by further evaluation of cell viability, cell cycle and apoptosis. Cell cycle and apoptosis were observed by using flow cytometry and the key regulatory proteins were detected by western blotting. Colony formation assessment and EdU assay were adopted to check cell proliferation. Results: TNFAIP3 expression was downregulated in lung cancer tissues at both mRNA and protein levels, comparing with that in adjacent non-tumor tissues. Consequently, the colony formation ability of lung cancer cells was enhanced, and the number of EdU positive lung cancer cells was increased. By contrast, elevated TNFAIP3 expression resulted in decreased colony formation ability of lung cancer cells. Mechanistically, TNFAIP3 overexpression rendered cell cycle of lung cancer cells halted at G0/G1 phase and caused apoptosis of lung cancer cells.Conclusion: Our data suggested that TNFAIP3 exhibits tumor suppressive roles in lung cancer.

Long noncoding RNA NEAT1 promotes the growth of cervical cancer cells via sponging miR-9-5p

2019 ◽  
Vol 97 (2) ◽  
pp. 100-108 ◽  
Author(s):  
Qiuxian Xie ◽  
Shanna Lin ◽  
Manjia Zheng ◽  
Qiutao Cai ◽  
Ya Tu
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Noncoding Rna ◽  
Inhibitory Effect ◽  
Micro Rna ◽  
Cancer Cell Growth ◽  
Cervical Cancer Cells ◽  
And Migration ◽  
Cancer Tissues ◽  
Competitive Endogenous Rna

Evidence has accumulated demonstrating that long noncoding RNAs (lncRNAs) participate in the initiation and progression of cancers. In this study, we found that the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) is significantly increased in both cervical cancer tissues and cell lines. Overexpression of NEAT1 promoted the proliferation and migration of cervical cancer cells. Molecular studies uncovered that NEAT1 functions as competitive endogenous RNA (ceRNA), binding the micro-RNA miR-9-5p and suppressing its expression. However, we consistently found that when NEAT1 was highly expressed, it attenuated the inhibitory effect of miR-9-5p on the expression of PTEN and POU2F1, which are the targets of miR-9-5p. Consistent with the negative regulation of NEAT1 on miR-9-5p, restoration of miR-9-5p inhibited the growth-promoting effects of NEAT1 on cervical cancer cells. Taken together, these results indicated that NEAT1 plays an important role in the regulation cervical cancer cell growth by targeting miR-9-5p. Our findings characterized the possible mechanism of NEAT1 in cervical cancer.

The long non-coding RNA CRNDE promotes cervical cancer cell growth and metastasis

2017 ◽  
Vol 399 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Yuanyuan Meng ◽  
Qi Li ◽  
Lianwei Li ◽  
Rong Ma
Keyword(s):  
Cervical Cancer ◽  
Wound Healing ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Wound Healing Assay ◽  
Transwell Assay ◽  
Cancer Cell Growth ◽  
Cervical Cancer Cells ◽  
Cancer Tissues

AbstractThis study was intended to analyze effects of lncRNA CRNDE on cervical cancer cell growth and metastasis. Fifty pairs of cervical cancer tissues and corresponding adjacent tissues were collected. Expressions of long non-coding RNAs (lncRNAs) in tissue samples were detected by microarray analysis. Expression levels of CRNDE in cervical cancer cells and normal cells were detected by qRT-PCR. Cell-counting kit-8 (CCK-8) assay and clone formation assay were utilized to evaluate cell growth. Wound healing assay and Transwell assay were conducted to detect the migratory and invasive capability of cervical cancer cells. The expressions of CRNDE in cervical cancer tissues and cells were higher than those in normal tissues and cells. CCK-8 assay and clone formation assay showed that the knockdown of CRNDE could inhibit the cell proliferation of HeLa and C-33A cells. Wound healing assay indicated that the downregulation of CRNDE expression could suppress the cell migration. The result of a Transwell assay demonstrated that the number of invasion cells reduced in the CRNDE-si group in comparison with the Mock group. LncRNA CRNDE could promote the cell growth and stimulate the metastasis of cervical cancer cells.

scholarly journals Increased Expression of eEF1A2 and PI3K-Akt Signaling Pathway Genes Promotes The Progression of Cervical Cancer

2021 ◽  
Author(s):  
Huizhen Xin ◽  
Huan Pan ◽  
Xiangyi Zhe ◽  
Chunhe Zhang ◽  
Hongtao Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Protein Expression ◽  
Akt Signaling ◽  
Cancer Development ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Qrt Pcr ◽  
Cervical Cancer Development ◽  
Cancer Tissues ◽  
Chronic Cervicitis

Abstract Objective: This study sought to explore the mRNA and protein expression levels of eukaryotic translation elongation factor 1 alpha 2 (eEF1A2) and members of the PI3K-Akt signaling pathway in the context of cervical cancer. We sought to clarify the expression of eEF1A2, PI3K, Akt during cervical cancer tumorigenesis and development.Methods: Samples from 72 cases of cervical cancer were collected, as well as 46 cases of cervical intraepithelial neoplasia (CIN), which reflects the continuous process of cervical cancer development, divided into CIN I, CIN II, CIN III, and 40 cases of chronic cervicitis. qRT-PCR was to detect the mRNA levels of eEF1A2, PI3K, and Akt, with β-actin used as an internal control. eEF1A2, PI3K, p-Akt protein levels in cervical cancer, CIN, and chronic cervicitis tissues were detected by immunohistochemical. eEF1A2, PI3K and p-Akt protein expression levels in HeLa, SiHa, and human umbilical vein endothelial cells were detected by western blot.Results: qRT-PCR results showed that the level of mRNA expression of eEF1A2, PI3K, and Akt was higher in cervical cancer tissues than that in normal cervical tissues. Immunohistochemistry results showed that the eEF1A2, PI3K, and p-Akt protein levels were higher in cervical cancer tissues than in cervical chronic cervicitis tissues. The differences were statistically significant (P < 0.05). The expression of eEF1A2, PI3K, and p-Akt protein was higher in HeLa and SiHa cervical cell lines than that in normal epithelial cells.Conclusion: Together, these results suggest that the aberrant expression of eEF1A2, PI3K, and Akt may play a role in cervical cancer development and tumorigenesis.

scholarly journals MicroRNA-200c Overexpression in Cancer-Associated Fibroblasts Reduces the Invasive Properties of Breast Cancer Cells: An Approach to Molecular Therapy

2021 ◽  
Author(s):  
Nasim Shenavar ◽  
Laleh Shariati ◽  
Mohammad Reza Hakimian ◽  
Shaghayegh Haghjooy Javanmard
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Critical Role ◽  
Molecular Therapy ◽  
Cancer Development ◽  
Cancer Associated Fibroblasts ◽  
Cancer Breast ◽  
Aggressive Subtype ◽  
Common Malignancy

Abstract BackgroundThe most common malignancy is breast cancer, among women in the world. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Cancer associated fibroblasts (CAFs) play a critical role to support tumor cells in all aspect of cancer development such as cell proliferation, migration and angiogenesis. MiRNAs are one of the regulatory molecules that regulate the genes contributing to cell growth, differentiation, migration and apoptosis. Based on other studies, miR-200c, as a tumor suppressor, has low expression levels in cancer associated fibroblasts. In this investigation, effect of miR-200c overexpression was evaluated on proliferation, migration and angiogenesis of TNBC cells. MethodsThe fibroblasts were isolated from normal and cancer breast tissue. MiR-200c expression was assessed using RT PCR in cancer associated fibroblasts (CAFs) and normal fibrobalasts (NFs) and then, were transfected using miR-200c. Finally, its effect on proliferation, migration and angiogenesis of TNBC cells were evaluated. ResultsOur results confirm that in presence of miR-200c transfected fibroblasts, the proliferation, migration and angiogenesis of cancer cells significantly decreased. This effect may be due to the reduction of growth factors provided by CAFs after miRNAs dysregulation. ConclusionThese results suggest miR-200c act as an effective tumor suppressor in many aspects of TNBC cancer development and can be regarded as a potential therapeutic tool for breast cancer in the future.

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