ABSTRACT
OBJECTIVE: This study aims to investigate the patient-reported outcomes (PROs) and complications of distinct implant-based breast reconstruction modality for patients with postmastectomy radiation therapy (PMRT). METHODS: A retrospective review was conducted on breast cancer patients with stage II-III disease who performed implant-based breast reconstruction following with PMRT between September 2016 and April 2022. The patients were categorized into two matched groups: (1) patients receiving prepectoral breast reconstruction (PBR) or (2) subpectoral breast reconstruction (SBR) followed by PMRT. Following reconstruction, the patients were further compared for PMRT with the tissue expander (PMRT-TE) versus PMRT with permanent implant (PMRT-PI). PROs were measured with BREAST-Q questionnaire. Early and late complications were recorded and analyzed. RESULTS: A total of 55 eligible patients were recruited. Patients who underwent PBR reported significantly higher satisfaction with breasts scores (P = 0.003) compared with the SBR group. The PMRT-TE group had higher satisfaction with breasts (P = 0.001) but lower physical well-being (P = 0.029) scores compared with PMRT-PI group. Moreover, patients in SBR cohort had a higher risk of capsular contracture (Baker grade III or IV) (20.5% vs 6.3%) and implant dislocation (48.7% vs 12.5%) than patients in PBR cohort. Patients in PMRT-PI group had a slightly higher rate of capsular contracture (Baker grade III or IV) than PMRT-TE group (20.8% vs 12.9%). CONCLUSIONS: PBR was associated with lower rates of late complications, especially for implant dislocation, and higher satisfaction with breasts scores compared to SBR. In addition, compared to PMRT-TE with PMRT-PI, patients in PMRT-TE cohort reported superior PROs of satisfaction with breasts.
Subject(s)
Breast Implantation , Breast Implants , Breast Neoplasms , Mastectomy , Patient Reported Outcome Measures , Postoperative Complications , Humans , Female , Retrospective Studies , Middle Aged , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Breast Implantation/methods , Breast Implantation/instrumentation , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Adult , Radiotherapy, Adjuvant , Patient Satisfaction , Mammaplasty/methodsABSTRACT
Cancer-associated fibroblasts (CAFs), the main stromal component of the tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms of regulated cell death (RCD) in adjacent tumor cells, thus involving cancer proliferation, therapy resistance, and immune exclusion. Here, we present a brief introduction to CAFs and basic knowledge of RCD, including apoptosis, autophagy, ferroptosis, and pyroptosis. In addition, we further summarize the different types of RCD in tumors that are mediated by CAFs, as well as the effects of these modes of RCD on CAFs. This review will deepen our understanding of the interactions between CAFs and RCD and might offer novel therapeutic avenues for future cancer treatments.
ABSTRACT
Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.
Subject(s)
Lung Neoplasms , MicroRNAs , Receptors, Complement , Animals , Humans , Mice , Antibodies , Antibodies, Blocking , Complement C1q , Immunity , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Receptors, Complement/geneticsABSTRACT
Background: Serum exosome-based liquid biopsy has significant advantages for screening and diagnosing hepatocellular carcinoma (HCC). P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are novel small silencing RNAs that have been identified to function in cancer-related signalling pathways. However, studies on the presence of piRNAs in serum exosomes from HCC patients and their diagnostic values in HCC are not well reported. Our aim is to validate serum exosome-derived piRNAs as the valuable component of liquid biopsy for diagnosing HCC. Methods: We used small RNA (sRNA) sequencing to profile piRNAs from serum exosomes and describe the base distribution characteristics of serum exosome-derived piRNAs. Serum exosomes from 125 HCC patients and 44 nontumor donors were included in this study. Results: We found that piRNAs were components of serum exosomes from HCC patients. A total of 253 differentially expressed serum exosome-derived piRNAs were screened from HCC compared with the piRNAs from nontumor donors. Serum exosome-derived piRNAs from HCC displayed a distinctive base distribution. To further confirm the potential diagnostic value of serum exosome-derived piRNAs in HCC, we detected the levels of the top 5 upregulated piRNAs in our Chinese cohort. The training set and validation set both showed that all 5 piRNAs were dramatically increased in the serum exosomes from HCC compared with the piRNAs from non-tumour donors. The piRNAs could strongly identify HCC patients from non-tumour donors according to the area under the receiver operating characteristic (AUROC) model. Additionally, the piRNAs could also present significant values for the diagnosis of HCC with low tumour burden. Conclusion: piRNAs enriched the components of serum exosomes from HCC and could serve as promising biomarkers for HCC diagnosis.
Subject(s)
Carcinoma, Hepatocellular , Exosomes , Liver Neoplasms , Male , Humans , Carcinoma, Hepatocellular/genetics , Piwi-Interacting RNA , Liver Neoplasms/genetics , Exosomes/metabolism , Biomarkers/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolismABSTRACT
Pyroptosis is a lytic and inflammatory type of programmed cell death that is mediated by Gasdermin proteins (GSDMs). Attractively, recent evidence indicates that pyroptosis involves in the development of tumors and can serve as a new strategy for cancer treatment. Here, we present a basic knowledge of pyroptosis, and an overview of the expression patterns and roles of GSDMs in breast cancer. In addition, we further summarize the available evidence of pyroptosis in breast cancer progression and give insight into the clinical potential of applying pyroptosis in anticancer strategies for breast cancer. This review will deepen our understanding of the relationship between pyroptosis and breast cancer, and provide a novel potential therapeutic avenue for breast cancer.
ABSTRACT
Neobavaisoflavone (Neo), as a traditional Chinese medicine, is the active ingredient in the herb Psoralea corylifolial and has antitumor activity. Myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of haematopoietic cells of the myeloid lineage, have been reported to be closely related to the pathogenesis of tumour progression, but whether Neo can regulate MDSC expansion and function remains unclear. Here, we found that Neo could inhibit the expansion and suppressive function of MDSCs by targeting STAT3. Importantly, Neo inhibited the growth of 4T1 and LLC tumours in vivo, as well as lung metastasis of 4T1 tumours in vivo. Furthermore, we identified MDSCs as the direct targets by which Neo attenuated tumour progression. In addition, Neo notably enhanced anti-PD-1 efficacy in anti-PD-1-insensitive 4T1 tumours. Therefore, our study sheds light on the development of Neobased therapeutic strategies against cancer.
Subject(s)
Isoflavones , Lung Neoplasms , Myeloid-Derived Suppressor Cells , Humans , Immunosuppression Therapy , Isoflavones/pharmacology , Isoflavones/therapeutic useABSTRACT
Breast cancer remains one of the most common malignancies in female cancer patients. The rapid and accurate diagnosis of human epidermal growth factor receptor 2 (HER2) status is indispensable for breast cancer patients. The pre-miR-4728 (mir-4728) is encoded within an intron of the HER2 gene. We showed here that mir-4728 was the most significantly upregulated pre-miRNA in HER2-positive breast cancer patients (fold-change: 4.37), and it could serve as a strong diagnostic factor for the HER2 status in breast cancer patients (p < 0.0001). Moreover, mir-4728 was positively correlated with tumor recurrence and appeared to be a critical independent risk factor of tumor recurrence in patients with high tumor burden (HR: 7.558, 95% CI:1.842-31.006, p = 0.005). Remarkably, HER2-positive patients with higher mir-4728 expression levels had better drug responses to targeted therapies. Furthermore, estrogen receptor (ESR), the predictive marker for endocrine therapies, was found to be the direct target of miR-4728-3p. Taken together, our results supported the potential role of mir-4728 in the diagnosis of HER2 status and the prognostic assessment of HER2-positive patients in response to targeted therapies.
ABSTRACT
TGF-ß is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-ß can greatly enhance antitumor immunity. However, there are still no effective TGF-ß inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-ß, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-ß at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-ß to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-ß at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-ß. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-ß regulation and implicate UDCA as a potential TGF-ß inhibitor to enhance antitumor immunity.
Subject(s)
Neoplasms , Transforming Growth Factor beta , Animals , Cell Line, Tumor , Humans , Immunosuppression Therapy , Mice , Neoplasms/drug therapy , Retrospective Studies , Transforming Growth Factor beta/metabolism , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/therapeutic useABSTRACT
BACKGROUND: Serum exosomes are emerging as key liquid biopsy biomarkers for the early diagnosis of cancer. However, the proportion and distribution of small RNA (sRNA) species from serum exosomes of hepatocellular carcinoma (HCC) patients remain unclear. Effective and reliable biomarkers for HCC diagnosis should be explored. METHODS: In this study, we aimed to use sRNA sequencing to profile the sRNAs of serum exosomes in HCC and non-tumor donors. The serum exosomes of 124 HCC patients and 46 non-tumor donors were enrolled for detecting the values of the potential biomarkers for the diagnosis of HCC. RESULTS: We found that miRNAs accounted for the maximal percentage of all types of sRNAs both in the serum exosomes of HCC patients and non-tumor donors. This indicated that the serum-exosome-derived microRNAs (miRNAs) were the most valuable as potential biomarkers in HCC diagnosis. Then, miRNAs were set as research candidates. In our Chinese cohorts, three serum-exosome-derived miRNAs (miR-122-5p, let-7d-5p, and miR-425-5p) could be promising biomarkers for distinguishing HCC patients from non-tumor donors. In addition, they were preferred for the early diagnosis of HCC. We also presented the base distribution of some novel serum-exosome-derived miRNAs and described the potential values as biomarkers. CONCLUSIONS: The results suggested that the serum-exosome-derived miRNAs were the most crucial sRNA species and they highlighted the potential of serum-exosome-derived miRNAs as promising biomarkers for HCC diagnosis.
ABSTRACT
Neobavaisoflavone (Neo), is the active constituent of the herb Psoralea corylifolial, used in the traditional Chinese medicine, and has anti-inflammatory activity, but whether Neo could regulate colitis remains unclear. T helper 9 (TH9) cells, a subset of CD4+ T helper cells characterized by secretion of IL-9, have been reported to be involved in the pathogenesis of many autoimmune and inflammatory diseases, but whether Neo could control TH9 cell differentiation also remains unclear. Here, we found that Neo could decrease IL-9 production of CD4+ T cells by targeting PU.1 in vitro. Importantly, Neo had therapeutic effects on DSS-induced colitis. Furthermore, we identified TH9 cells as the direct target of Neo for attenuating bowel inflammation. Therefore, Neo could serve as a lead for developing new therapeutics against inflammatory bowel disease.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cell Differentiation/drug effects , Colitis/drug therapy , Isoflavones/therapeutic use , T-Lymphocytes, Helper-Inducer/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Colitis/immunology , Female , Fluorescent Antibody Technique , Humans , Immunoblotting , Isoflavones/pharmacology , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Real-Time Polymerase Chain ReactionABSTRACT
Schisandrin B (Sch B) is the major active ingredient of the traditional Chinese medicine Schisandra chinensis and has antitumor activity, anti-inflammatory activity. CD4+ Th subsets orchestrate immune responses to plenty of pathogen infections and participate in the pathogenesis of many immune-related diseases. However, little is known about the relationship between Sch B and T cell differentiation. Here, we showed that Sch B might participate in T cell receptor signaling pathway by using the TCMIO database. Importantly, Sch B promoted TH1 cell differentiation. Furthermore, Sch B did not affect TH2 cell and Treg differentiation. Mechanismly, Sch B increased the level of IFN-γ of CD4+ T cells by upregulating the phosphorylation of STAT1 protein. Then, STAT1 promoted T-bet expression in CD4+ T cells. In conclusion, Sch B modulates the differentiation of naïve CD4+ T cells into TH1 subset by STAT1/T-bet signaling, which may have the potential for the treatment of T cell-mediated-immune diseases.
Subject(s)
Cell Differentiation/drug effects , Lignans/pharmacology , Polycyclic Compounds/pharmacology , STAT1 Transcription Factor/metabolism , Th1 Cells/drug effects , Animals , B-Lymphocytes/drug effects , Cyclooctanes/pharmacology , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Female , Fluorescent Antibody Technique , Immunoblotting , Interferon-gamma/metabolism , Interleukin-4/metabolism , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , STAT1 Transcription Factor/drug effectsABSTRACT
Schisandrin B (Sch B) is the major active constituent of the traditional Chinese medicine Schisandra chinensis and has anti-inflammatory activity, but the target of Sch B remains unclear. T helper 17 (TH17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases. Here, we showed that Sch B could decrease IL-17A production of CD4+ T cells by targeting STAT3 in vitro. Importantly, Sch B has therapeutic effects on DSS-induced acute and chronic colitis, CD4+CD45RBhigh T cell-induced colitis. Furthermore, we identified TH17 cells as the direct target of Sch B for mediating its anti-inflammatory activity. Sch B could serve as a lead for developing new therapeutics against TH17 cells or IL-17A cytokine-driven diseases.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Lignans/therapeutic use , Polycyclic Compounds/therapeutic use , Th17 Cells/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Cell Differentiation/drug effects , Cells, Cultured , Cyclooctanes/pharmacology , Cyclooctanes/therapeutic use , Female , Humans , Inflammatory Bowel Diseases/pathology , Lignans/pharmacology , Mice, Inbred C57BL , Polycyclic Compounds/pharmacology , Th17 Cells/pathologyABSTRACT
Tumors escape immune attack by upregulating the surface expression of PD-L1, which interacts with PD-1 on T cells to activate immune inhibitory signaling. Anti-PD-1 treatments can effectively block this inhibitory signaling and activate antitumor immune responses. However, anti-PD-1 treatment also has a tumor suppressive effect in patients whose tumor cells do not express PD-L1. The underlying mechanisms are poorly defined. Here, we report that exosomes from bone marrow-derived cells (BMDCs) in tumor-bearing mice, but not in healthy mice, carry PD-L1. PD-L1 on these exosomes is biofunctional and can inhibit CD8+ T cell proliferation and activation in vitro and in vivo. The transfer of exogenous exosomes from BMDCs and the inhibition of the production of endogenous exosomes by BMDCs promote and suppress tumor growth, respectively. PD-L1+ exosomes from BMDCs can be found in tumor tissues. In addition, exosomes from BMDCs promote tumor metastasis in a PD-L1-dependent manner. Therefore, our results indicate that exosomes from BMDCs play important roles in tumor immunosuppression via PD-L1.
Subject(s)
B7-H1 Antigen , Exosomes , Animals , B7-H1 Antigen/metabolism , Bone Marrow/metabolism , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Exosomes/metabolism , Humans , Immune Tolerance , MiceABSTRACT
The Chinese herbal medicine oridonin has potent anti-inflammatory and antitumor activities. In addition, oridonin treatment effectively suppresses breast cancer growth. However, the underlying mechanisms are poorly defined. Here, we reported that oridonin decreased Treg differentiation in vitro and in vivo. Oridonin inhibition of Treg differentiation was dependent on decreasing TGF-ß receptor expression. Oridonin attenuated Tregs' immunosuppressive ability; thus, oridonin did not inhibit CD8+ T cell proliferation very well in vitro. Oridonin greatly delayed the progression of 4T1 tumors in vivo. In addition, oridonin combined with anti-PD-1 activated a robust antitumor immune response and suppressed 4T1 tumor growth. Therefore, our results indicate that oridonin inhibits TNBC growth by modulating Treg differentiation, which provides new directions for the clinical treatment of TNBC.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Differentiation/drug effects , Diterpenes, Kaurane/pharmacology , Receptors, Transforming Growth Factor beta/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Antineoplastic Agents/therapeutic use , Breast Neoplasms/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Diterpenes, Kaurane/therapeutic use , Drug Therapy, Combination , Female , Humans , Mice, Inbred BALB C , Mice, Nude , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes, Regulatory/drug effectsABSTRACT
With the improved understanding of the molecular pathogenesis and characteristics of cancers, the critical role of the immune system in preventing tumor development has been widely accepted. The understanding of the relationship between the immune system and cancer progression is constantly evolving, from the cancer immunosurveillance hypothesis to immunoediting theory and the delicate balance in the tumor microenvironment. Currently, immunotherapy is regarded as a promising strategy against cancers. Although adoptive cell therapy (ACT) has shown some exciting results regarding the rejection of tumors, the effect is not always satisfactory. Cellular therapy with CD4+ T cells remains to be further explored since the current ACT is mainly focused on CD8+ cytotoxic T lymphocytes (CTLs). Recently, Th9 cells, a subgroup of CD4+ T helper cells characterized by the secretion of IL-9 and IL-10, have been reported to be effective in the elimination of solid tumors and to exhibit superior antitumor properties to Th1 and Th17 cells. In this review, we summarize the most recent advances in the understanding of Th9 cell differentiation and the dual role, both anti-tumor and pro-tumor effects, of Th9 cells in tumor progression.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cancer Vaccines/immunology , Carcinogenesis/immunology , Immunotherapy, Adoptive/methods , Interleukin-9/metabolism , Neoplasms/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Cell Differentiation , Humans , Immunity, Cellular , Lymphocyte Activation , Neoplasms/therapyABSTRACT
BACKGROUND: The exact biological role of PCOLCE was not yet clear and there were few reports study the correlation of PCOLCE gene expression level with the occurrence and development of gastric cancer. METHODS: The expression of PCOLCE was analyzed by performing the Oncomine and Ualcan database. We evaluated the function of PCOLCE on clinical prognosis with the use of Kaplan-Meier plotter database. The relationship between PCOLCE and cancer immune in filtrates was researched by Tumor Immune Estimation Resource (TIMER) site database. RESULTS: PCOLCE significantly upregulated in gastric cancer patients compared to normal gastric samples. And the increased expression of PCOLCE mRNA was closely linked to shorter overall survival (OS), progress-free survival (PFS) in all gastric cancers. Besides, PCOLCE expression displayed a tight correlation with infiltrating levels of macrophages and dendritic cells (DCs) in gastric cancer. Moreover, PCOLCE expression was positively correlated with diverse immune marker sets in gastric cancer. CONCLUSION: All the results above suggested that overexpression of PCOLCE indicated unfavorable prognosis in patients with gastric cancer. PCOLCE was correlated with immune infiltrating levels including those of B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and DCs in gastric cancer patients. All the findings suggested that PCOLCE could be used as a prognostic biomarker for determining prognosis and immune infiltration in gastric cancer. Additionally, PCOLCE expression potentially contributed to the regulation of monocyte, M2 macrophage, Tfh, CD8 + T cell, TAM, Th1 cell Thus PCOLCE is a potential target for gastric cancer therapy and these preliminary findings require further study to determine whether PCOLCE-targeting reagents might be developed for clinical application in gastric cancer.
ABSTRACT
Purpose: The removal of the giant breast fibroadenoma (GFA) with esthetic repair of the severe deformed breast is a surgical challenge. Materials and Methods: This was a retrospective study of data of 10 patients with GFAs who treated with a modified round block technique at the Department of Breast Surgery, Hangzhou First People's Hospital (Hangzhou, Zhejiang province, China) from March 2014 to June 2017. Preoperatively, according to the degree of excess skin and asymmetry, a four-point approach was designed. The area between the inner and outer circles was de-epidermized. The tumors were entirely stripped off along the capsule through an incision on a part of the outer circle. To avoid the nipple-areola complex widening, purse-string suture technique was used. Results: Patients' age ranged from 12 to 32 years (mean age, 23 years), and the largest tumor weighed 2 kg, with a diameter of 16.5 cm. After a mean follow-up of 25 months (range, 9-32 months), no local recurrences were found. Cosmetic results were satisfactory with breast symmetry and minimal scarring. Complications were minimal and widening of the periareolar scar was slight as well. Conclusion: The modified round block technique is recommended to resect GFA in order to improve the cosmetic results with minimal scar.
Subject(s)
Breast Neoplasms/surgery , Breast/pathology , Cicatrix/diagnosis , Fibroadenoma/surgery , Mastectomy, Segmental/methods , Adolescent , Adult , Breast/diagnostic imaging , Breast/surgery , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Child , China , Cicatrix/etiology , Cicatrix/prevention & control , Esthetics , Female , Fibroadenoma/diagnosis , Fibroadenoma/pathology , Humans , Magnetic Resonance Imaging , Mastectomy, Segmental/adverse effects , Nipples/surgery , Patient Satisfaction , Retrospective Studies , Severity of Illness Index , Suture Techniques , Treatment Outcome , Ultrasonography, Mammary , Young AdultABSTRACT
Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.
Subject(s)
Cell Differentiation , Inflammatory Bowel Diseases/immunology , Signal Transduction , T-Lymphocytes, Regulatory/cytology , fas Receptor/immunology , Animals , Cytokines/genetics , Cytokines/immunology , Female , Humans , Inflammatory Bowel Diseases/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , NF-kappa B/genetics , NF-kappa B/immunology , NFATC Transcription Factors/genetics , NFATC Transcription Factors/immunology , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/therapy , Protein Kinase C beta/genetics , Protein Kinase C beta/immunology , T-Lymphocytes, Regulatory/immunology , fas Receptor/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/immunologyABSTRACT
BACKGROUND: MicroRNAs (miRNAs) play an essential role in the initiation, progression and metastasis of breast cancer. It has been confirmed that miR-30b is involved in various cancers. However, the specific involvement of miR-30b on breast cancer metastasis remains unknown. In the current study, we aimed to investigate the role of miR-30b in the progression and metastasis of breast cancer in vitro. METHODS: We up-regulated the expression of miR-30b in breast cancer cell lines SKBR3 and MDA-MB-231 by transfecting pCMV-miR-30b vector. CCK8, colony formation, Transwell, and flow cytometry assays were used to examine cell proliferation, migration, invasion and apoptosis, respectively. A dual-luciferase reporter assay was performed to identify the relationship between miR-30b and the target gene. Western blot assay was used to detect related proteins. RESULTS: Our data showed that the overexpression of miR-30b significantly inhibited proliferation, migration and invasion abilities in SKBR3 and MDA-MB-231 cells. Meanwhile, overexpression of miR-30b induced cell apoptosis for both SKBR3 and MDA-MB-231 cells by regulating the expression of apoptosis-related proteins (Bcl-2, Bax, active Caspase-3, and Caspase-9). Moreover, miR-30b inhibited the activation of the PI3K/Akt signaling pathway by decreasing the phosphorylation levels of Akt and mTOR. Furthermore, we determined that miR-30b could down-regulate the expression of Derlin-1 in a post-transcriptional manner by employing the dual-luciferase reporter and western blot assays. Further analysis demonstrated that depletion of Derlin-1 inhibited Akt phosphorylation, and Derlin-1 could restore the effect of miR-30b on Akt. In addition, the CCK8 assay showed that Derlin-1 could partly reverse the inhibition of cell proliferation of SKBR3 and MDA-MB-231 cells mediated by miR-30b. CONCLUSIONS: Our data demonstrated that miR-30b suppresses the progression and metastasis of breast cancer via inhibition of the PI3K/Akt signaling pathway by targeting Derlin-1 in vitro. This suggests that miR-30b might be a novel potent target for breast cancer therapy.
ABSTRACT
Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression.