scholarly journals TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway

Author(s):  
Xun Zhu ◽  
Xiaorong Liu ◽  
Yehui Zhou ◽  
Chenglin Qin

Abstract Background Worldwide, Breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer that PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. Methods and Result In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulate the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression that p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation, invasion, and promote apoptosis in breast cancer cells. Conclusions In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.


2021 ◽  
pp. 096032712198942
Author(s):  
Xiaoxue Zhang ◽  
Xianxin Xie ◽  
Kuiran Gao ◽  
Xiaoming Wu ◽  
Yanwei Chen ◽  
...  

As one of the leading causes of cancer-related deaths among women, breast cancer accounts for a 30% increase of incidence worldwide since 1970s. Recently, increasing studies have revealed that the long non-coding RNA ILF3-AS1 is involved in the progression of various cancers. Nevertheless, the role of ILF3-AS1 in breast cancer remains largely unknown. In the present study, we found that ILF3-AS1 was highly expressed in breast cancer tissues and cells. ILF3-AS1 silencing inhibited breast cancer cell proliferation, migration and invasion, and promoted cell apoptosis. ILF3-AS1 bound with miR-4429 in breast cancer cells. Moreover, RAB14 was a downstream target of miR-4429, and miR-4429 expression was negatively correlated with RAB14 or ILF3-AS1 expression in breast cancer tissues. The result of rescue experiments demonstrated that overexpression of RAB14 can reverse the inhibitory effect of ILF3-AS1 knockdown on breast cancer cell proliferation, migration and invasion. Overall, ILF3-AS1 promotes the malignant phenotypes of breast cancer cells by interacting with miR-4429 to regulate RAB14, which might offer a new insight into the underlying mechanism of breast cancer.


Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 688
Author(s):  
Jiawei Chen ◽  
Vivian Yvonne Shin ◽  
John Chi-Wang Ho ◽  
Man-Ting Siu ◽  
Isabella Wai-Yin Cheuk ◽  
...  

It is well-established that tumor-associated macrophages (TAMs) play an important role in breast cancer development. Accumulating evidence suggested that human cathelicidin antimicrobial protein (CAMP), which is mainly expressed in host defense cells such as macrophages, is crucial not only in combating microorganisms but also promoting tumor growth. Here we report the interaction of CAMP with TAMs in breast cancer. CAMP expression was upregulated in cancer tissues and in the circulation of breast cancer patients. Surgical removal of tumor decreased CAMP peptide serum level. Knockdown of CAMP decreased cell proliferation and migration/invasion ability in breast cancer cells. CAMP expression was altered during macrophage M1/M2 polarization and was expressed predominantly in M2 phenotype. In addition, breast cancer cells co-cultured with macrophages upregulated CAMP expression and also increased cancer cell viability. Xenograft tumors reduced significantly upon CAMP receptor antagonist treatment. Our data implicated that CAMP confers an oncogenic role in breast cancer and plays an important role in the tumor microenvironment between TAMs and breast cancer cells, and blocking the interaction between them would provide a novel therapeutic option for this malignant disease.


Author(s):  
Gehao Liang ◽  
Yun Ling ◽  
Qun Lin ◽  
Yu Shi ◽  
Qing Luo ◽  
...  

ObjectivesCircular RNA (circRNA) is a novel class of RNA, which exhibits powerful biological function in regulating cellular fate of various tumors. Previously, we had demonstrated that over-expression of circRNA circCDYL promoted progression of HER2-negative (HER2–) breast cancer via miR-1275-ULK1/ATG7-autophagic axis. However, the role of circCDYL in HER2-positive (HER2+) breast cancer, in particular its role in modulating cell proliferation, one of the most important characteristics of cellular fate, is unclear.Materials and methodsqRT-PCR and in situ hybridization analyses were performed to examine the expression of circCDYL and miR-92b-3p in breast cancer tissues or cell lines. The biological function of circCDYL and miR-92b-3p were assessed by plate colony formation and cell viability assays and orthotopic animal models. In mechanistic study, circRNAs pull-down, RNA immunoprecipitation, dual luciferase report, western blot, immunohistochemical and immunofluorescence staining assays were performed.ResultsCircCDYL was high-expressed in HER2+ breast cancer tissue, similar with that in HER2– breast cancer tissue. Silencing HER2 gene had no effect on expression of circCDYL in HER2+ breast cancer cells. Over-expression of circCDYL promoted proliferation of HER2+ breast cancer cells but not through miR-1275-ULK1/ATG7-autophagic axis. CircRNA pull down and miRNA deep-sequencing demonstrated the binding of miR-92b-3p and circCDYL. Interestingly, circCDYL did not act as miR-92b-3p sponge, but was degraded in miR-92b-3p-dependent silencing manner. Clinically, expression of circCDYL and miR-92b-3p was associated with clinical outcome of HER2+ breast cancer patients.ConclusionMiR-92b-3p-dependent cleavage of circCDYL was an essential mechanism in regulating cell proliferation of HER2+ breast cancer cells. CircCDYL was proved to be a potential therapeutic target for HER2+ breast cancer, and both circCDYL and miR-92b-3p might be potential biomarkers in predicting clinical outcome of HER2+ breast cancer patients.


2021 ◽  
Vol 11 (12) ◽  
pp. 2472-2477
Author(s):  
Chunxiong Fan ◽  
Yanping Deng ◽  
Yaqing Liu ◽  
Xiaoying Liu ◽  
Xi Ke ◽  
...  

Our study assessed miR-556-3p’s role in breast cancer cells. A total of 65 cases of breast cancer tissue samples were retrospectively analyzed to detect miR-556-3p level by PCR and analyze survival time and 30 normal breast tissues were included as a control group. Breast cancer cells were cultured followed by analysis of cell proliferation by MTT, cell invasion by transwell assay. miR-556-3p level was significantly upregulated in breast cancer patients compared to control group (P <0.05) and inversely associated with survival rate (P <0.05). In vitro experiments, cell activity and invasion were positively correlated with miR-556-3p level (P <0.05). In MCF-7 cell lines, miR-556-3p overexpression increased cell activity (P <0.05). Meanwhile, after miR-556-3p was overexpressed, the expression of DAB2IP, Erk, p-Erk in breast cancer cells was significantly reduced and increased after miR-556-3p was knocked down. In conclusion, miR-556-3p targets DAB2IP3′-UTR, promotes breast cancer cell proliferation, indicating that miR-556-3p might be involved in breast cancer pathogenesis and may be a new target for the treatment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Qin Huo ◽  
Siqi Chen ◽  
Zhenwei Li ◽  
Juan Wang ◽  
Jiaying Li ◽  
...  

Accumulating evidences indicate that transforming acidic coiled-coil 3 (TACC3) is a tumor-related gene, was highly expressed in a variety of human cancers, which is involved in cancer development. However, the potential role of TACC3 in breast cancer remains largely unknown. In the present study, we found that TACC3 was highly-expressed in breast cancer tissues, and its level was positively correlated with the clinical features of breast cancer patients. Specifically, TACC3 expression was significantly associated with the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, nodal status, the scarff-bloom-richardson (SBR) grade, nottingham prognostic index (NPI), age, subtypes, and triple-negative and basal-like status, suggesting that TACC3 may be a potential diagnostic indicator of breast cancer. Furthermore, functional studies have shown that inhibition of TACC3 can significantly promote the cell proliferation and viability of breast cancer cells. Moreover, TACC3 knockdown suppressed the expression of E-cadherin, but increased the expression of N-cadherin, Snail, ZEB1, and TWIST, which indicate that TACC3 may impact the migration of breast cancer cells in vitro. Taken together, these findings indicate that TACC3 may serve as a prognostic and therapeutic indicator of breast cancer.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6112
Author(s):  
Aram Lee ◽  
Soyoung Lim ◽  
Juyeong Oh ◽  
Jihyun Lim ◽  
Young Yang ◽  
...  

(1) Background: The aim of the present study was to evaluate the effect of NDRG2 expression in regulating PD-L1 or PD-L2 on malignant breast cancer cells. (2) Methods: Overexpression and knockdown of the NDRG2 gene in human and mouse cancer cells were applied and quantitative real-time PCR and Western blot analysis were performed. T cell proliferation and TCGA analysis were conducted to validate negative correlation of the PD-L1 expression with the NDRG2 expression. (3) Results: We found that NDRG2 overexpression inhibits PD-L1 expression in human breast cancer cells through NF-κB signaling. NDRG2 overexpression in 4T1 mouse breast cancer cells followed by PD-L1 downregulation could block the suppressive activity of cancer cells on T cell proliferation and knockdown of NDRG2 expression enhanced the expression of PD-L1, leading to the inhibition of T cell proliferation by tumor cell coculture. Finally, we confirmed from TCGA data that PD-L1 expression in basal and triple-negative breast cancer patients was negatively correlated with the expression of NDRG2. Intriguingly, linear regression analysis using TNBC cell lines showed that the PD-L1 level was negatively associated with the NDRG2 expression level. (4) Conclusions: Our findings demonstrate that NDRG2 expression is instrumental in suppressing PD-L1 expression and restoring PD-L1-inhibited T cell proliferation activity in TNBC cells.


2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Liwei Ruan ◽  
Xiaojun Qian

Abstract Background: Breast cancer endangers the life of women and has become the major cause of deaths among them. MiRNAs are found to exert a regulatory effect on the migration, proliferation and apoptosis of breast cancer cells. This research aims at investigating the miR-16-5p expression and its effect on the pathogenesis of breast cancer. Methods: Their clinical data were analyzed with qRT-PCR. CCK8, EdU and Transwell was performed to explore the function of miR-16-5p in cell migration and proliferation of breast cancer cells. Dual-luciferase reporter assay, immunohistochemistry and Western blotting were carried out to explore the relation between miR-16-5p and AKT3. Results: It was discovered that miR-16-5p was lowly expressed in breast cancer patients. Meanwhile, breast cancer patients with under-expressed miR-16-5p had a lower survival rate than those with highly expressed miR-16-5p. Furthermore, decreased miR-16-5p in cell and animal models enhanced migration and proliferation of breast cancer cells, stimulated cell cycle and reduced cell apoptosis. Finally, we found miR-16-5p restrained the NF-κB pathway and decreased AKT3 gene, thereby suppressing the breast cancer development. Conclusion: It can be seen that miR-16-5p exhibits a low expression in breast cancer tissues, which can inhibit breast cancer by restraining the NF-κB pathway and elevating reducing AKT3.


2021 ◽  
Author(s):  
Hongquan Lu ◽  
Zhenjia Jiang

Abstract Background: Accumulating evidence has suggested that long noncoding RNA (lncRNA) played crucial roles in the development of human malignances including breast cancer. SNHG19 is a newly identified lncRNA which exerted oncogenic function in non-small cell lung cancer, but whether SNHG19 was involved the development of other cancer, such as breast cancer still unclear. Methods: qRT-PCR was performed to examine the expression of SNHG19 and miR-299-5p in breast cancer tissues and cell lines. Cell proliferation was measure using CCK-8 and colony formation assay. Cell migration and invasion ability was detected by wound healing assay and transwell invasion assay. Bioinformatics analysis, dual luciferase reporter assay, RIP assay and Pull down assay were used to verify the direct binding between SNHG19 and miR-299-5p. The xenotransplantation mouse model was established to explore the effect of SNHG19 on breast cancer tumor growth in vivo.Results: We found that SNHG19 expression level was up-regulated in breast cancer tissues and cell lines, while miR-299-5p expression was down-regulated in breast cancer tissues and it was negatively correlated with SNHG19 expression. Silence of SNHG19 inhibited breast cancer cells proliferation, migration and invasion in vitro. Moreover, SNHG19 knockdown suppressed tumor growth of breast cancer cells in vivo. Mechanistically, SNHG19 acted as a ceRNA (competitive endogenous RNA) to sponge miR-299-5p. Finally, the rescue assays further confirmed that miR-299-5p inhibitor reversed the inhibitory effects of SNHG19 knockdown on breast cancer cell proliferation, migration and invasion.Conclusions: In conclusion, our findings proved that SNHG19 promoted breast cancer progression via sponging miR-299-5p and might function as promising prognostic indicator and therapeutic target for breast cancer.


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