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Numerous studies have indicated that N6-methyladenosine (m6A) and lncRNAs play pivotal roles in human cancer. However, the underlying functions and mechanisms of m6A-lncRNA in the physiological processes of breast cancer remain unclear. Here, we found that DSCAM-AS1 is an m6A-modified lncRNA that was overexpressed in breast cancer tissues and cells, indicating poor clinical prognosis. Gain/loss functional assays suggested that DSCAM-AS1 inhibited erastin-induced ferroptosis in breast cancer cells. Mechanistically, there were remarkable m6A modification sites on both the 3'-UTR of DSCAM-AS1 and the endogenous antioxidant factor SLC7A11. M6A methyltransferase methyltransferase-like 3 (METTL3) methylated both SLC7A11 and DSCAM-AS1. Moreover, DSCAM-AS1 recognized m6A sites on the SLC7A11 mRNA, thereby enhancing its stability. Taken together, these findings indicated a potential therapeutic strategy for breast cancer ferroptosis in an m6A-dependent manner.
Assuntos
Neoplasias da Mama , Ferroptose , Metiltransferases , RNA Longo não Codificante , Animais , Feminino , Humanos , Camundongos , Adenosina/análogos & derivados , Adenosina/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Ferroptose/genética , Metiltransferases/metabolismo , Metiltransferases/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Brain metastasis (BM) in laryngeal squamous cell carcinoma (LSCC) is uncommon but prognosis is poor. Anti-PD-1 immunotherapy benefits some advanced LSCC cases, yet its efficiency is limited by tumor complexity. We analyzed paired metastatic tumor samples from before and after immunotherapy using single-cell RNA sequencing (scRNA-seq), along with a primary LSCC dataset and bulk RNA sequencing. This identified changes post-immunotherapy and revealed differences in single-cell transcriptomes among LSCC, primBM, and neoBM. Our findings show that anti-PD-1 treatment suppresses metastasis-promoting pathways like VEGF and EMT in cancer cells, and alters immune cell functions. Notably, it upregulates T cell activation, leading to CD8 T cell exhaustion from excess heat shock proteins, notably HSPA8. However, CD8 T cell cytotoxic functions improve post-treatment. In myeloid cells, anti-PD-1 therapy enhances antigen presentation and promotes a proinflammatory shift post-metastasis. Additionally, NUPR1 is linked to BM in LSCC, and NEAT1 is a potential metastatic cancer cell cycle participant. Our study provides insights into cancer heterogeneity and the impact of PD-1 immunotherapy on metastasis, aiding precise diagnosis and prognosis.
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Background: Breast cancer has become the most frequently diagnosed cancer in the world. Detection at an early stage, frequently allows women to benefit from breast conserving surgery. However, some patients are not satisfied with the breast shape after breast-conserving surgery, and autologous tissue flaps are needed to fill the defect in the resection area. The modified lateral thoracic artery perforator (LTAP) flap isn't one of the commonly used flaps in breast surgery and has the advantages of a reliable blood supply, simple operation and few postoperative complications. In this study, we aimed to evaluate the feasibility and effectiveness of a modified LTAP flap for repairing partial breast defects after breast-conserving surgery. Methods: In this study, we retrospectively analyzed the clinical data of 126 patients treated with LTAP flaps to repair local breast defects at Affiliated Hospital of Guangdong Medical University between January 2020 and June 2021. Data were collected on the demographic characteristics of these patients, tumor size and location, type of axillary lymph node surgery, availability of adjuvant chemotherapy and radiotherapy, and postoperative complications. Results: The median weight of the tumor specimen was 185 g (range, 170-320 g), and this glandular tissue accounted for 30% to 40% of the total breast volume. The average flap size was 10.5 cm ×2.5 cm (length range, 8-15 cm, width range: 2-4 cm). The minimum follow-up time was 6 months, with an average of 10 months (range, 6-22 months). The mean operative time was 130 minutes (range: 90-180 minutes), and the mean hospital stay was 3 days (range, 2-5 days). All modified LTAP flaps survived completely without donor site complications. None of the patients required revision surgery on the postoperative breast. Conclusions: The modified LTAP flap is a reliable method for repairing partial breast defects after breast-conserving surgery. It has the advantages of a simple operation, a reliable blood supply, fewer postoperative complications, and a high flap survival rate. It is especially suitable for Asian women with small breast volumes and can achieve good breast contouring effects.
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Background: Breast cancer is the most common gynecological malignancy and the leading cause of cancer-related deaths in women. P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are novel non-coding RNAs whose abnormal expressions have been closely associated with multiple cancers. This study explored the roles and possible mechanisms of piRNA-31106 in breast cancer. Methods: The expression of piRNA-31106 in breast cancer tissues and cells was detected by reverse transcription polymerase chain reaction (RT-PCR). The pcDNA vector containing piRNA-31106 (pcDNA-piRNA-31106) and a short hairpin (sh)RNA containing piRNA-31106 (shRNA-piRNA-31106) were used to interfere with piRNA-31106 expression in breast cancer cells. The effects on cell proliferation, apoptosis/cell cycle, invasion, and metastasis were detected via Cell Counting Kit-8 (CCK-8), flow cytometry, transwell assays, and scratch tests, respectively. The protein expressions of murine double minute 2 (MDM2), cyclin-dependent kinase 4 (CDK4), and cyclinD1 were detected by Western blot analysis. The N6-methyladenosine (m6A) RNA methylation level and the binding relationship between piRNA-31106 and METTL3 were analyzed. The role of METTL3 in the regulation of breast cancer by piRNA-31106 was further analyzed by using small interfering (si)RNA targeting METTL3. Results: PiRNA-31106 was highly expressed in breast cancer tissues and cell lines MDA-MB-231 and MCF-7. Overexpression of piRNA-31106 promoted the viability, invasion, and migration of breast cancer, inhibited apoptosis, and promoted the expressions of MDM2, CDK4, and cyclinD1. Inhibition of piRNA-31106 showed the opposite effect. In addition, piRNA-31106 promoted the m6A methylation levels and facilitated methyltransferase-like 3 (METTL3) expression in MDA-MB-231 and MCF-7 cells. RNA immunoprecipitation (RIP) assays confirmed the binding relationship between piRNA-31106 and METTL3. Further experiments demonstrated that si-METTL3 could inhibit the regulatory effects of piRNA-31106 on breast cancer. Conclusions: PiRNA-31106 was significantly highly expressed in breast cancer and could promote breast cancer progression by regulating METTL3-mediated m6A RNA methylation.
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BACKGROUND: Chronic radiative chest wall ulcers are common in patients undergoing radiation therapy. If not treated early, then symptoms such as erosion, bleeding and infection will appear on the skin. In severe cases, ulcers invade the ribs and pleura, presenting a mortality risk. Small ulcers can be repaired with pedicle flaps. Because radioactive ulcers often invade the thorax, surgeons need to remove large areas of skin and muscle, and sometimes ribs. Repairing large chest wall defects are a challenge for surgeons. CASE SUMMARY: A 74-year-old female patient was admitted to our department with chest wall skin ulceration after radiation therapy for left breast cancer. The patient was diagnosed with chronic radioactive ulceration. After multidisciplinary discussion, the authors performed expansive resection of the chest wall ulcers and repaired large chest wall defects using a deep inferior epigastric perforator (DIEP) flap combined with a high-density polyethylene (HDPE) patch. The patient was followed-up 6 mo after the operation. No pigmentation or edema was found in the flap. CONCLUSION: DIEP flap plus HDPE patch is one of the better treatments for radiation-induced chest wall ulcers.
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BACKGROUND: In recent years, breast cancer is the most common malignancy in women. The traditional method of surgery is to remove a woman's breast completely, which has a negative impact on her work and life. Today, women have a fiery pursuit to maintain their perfect figure, which has forced breast surgeon to find a new surgical approach to maintain the shape of the breast after surgery. METHODS: This study systematically analyzed and summarized the incision design and repair of glandular defects in early-stage breast cancer patients by oncoplastic breast techniques. By summarizing the methods of oncoplastic breast surgery (OBS) in different quadrants, it could help beginners to master this technology more quickly, so as to provide better help for breast cancer patients. RESULTS: A total of 216 breast cancer patients who underwent OBS from January 2016 to June 2020 at the Affiliated Hospital of Guangdong Medical University were included in this study. In patients treated with the volume-displacement method and the volume-replacement method, 92.6% and 86.2% of patients achieved excellent breast shape, respectively. CONCLUSIONS: OBS is a safe and effective way to treat early-stage breast cancer while obtaining better breast shape, reducing postoperative psychological trauma, and improving quality of life.
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MicroRNA (miR)125a5p has shown the potential for suppressing tumorigenesis and development; however, the effects of miR125a5p on breast cancer cells remains unknown. The aim of this study was to evaluate the effects and underlying mechanisms of miR125a5p in MCF7 breast cancer cells. MCF7 cells were transfected with miR125a5p mimic or miR125a5p small interfering RNA to produce miR125a5p overexpressing/knockdown cells. Cell proliferation was assessed by an MTT assay, and cell migration ability was determined by an in vitro scratch assay. Hoechst 33258 staining and flow cytometry were performed to assess the effects of miR125a5p on MCF7 apoptosis. Western blotting and reverse transcriptionquantitative polymerase chain reaction were used for measuring phosphatase and tensin homolog (PTEN), phosphorylated (p)mitogenactivated protein kinase kinase (MEK1/2)/MEK1/2, pERK1/2/ERK1/2, Bcell lymphoma2 (Bcl2), cleaved caspase3, and miR125a5p expression. miR125a5p overexpression inhibited the proliferation and migration, but promoted the apoptosis of MCF7 cells. These effects were associated with increases in PTEN and cleaved caspase3 expression, and decreases in pMEK1/2/MEK1/2, pERK1/2/ERK1/2, and Bcl2. Silencing of miR125a5p exhibited opposing effects on MCF7 cells. These observations suggested that miR125a5p participates in the regulation of multiple functions of MCF7 cells by promoting the expression of PTEN tumor suppressor genes, activating MEK1/2/ERK1/2 signaling, and regulating caspase3/Bcl2 signaling. Thus, it may be a suitable target for breast cancer gene therapy.
Assuntos
Apoptose , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Células MCF-7 , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Neoplásico/genéticaRESUMO
Although a number of studies have been conducted on the association between HTR2A T102C polymorphism and major depressive disorder (MDD) in Chinese, this association remains elusive and controversial. To clarify the effects of HTR2A T102C polymorphism on the risk of MDD, a meta-analysis was performed in the Chinese population. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 5 May 2015. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations. Statistical analyses were conducted with Version 10.0 STATA statistical software. A total of 12 case-control studies including 1444 MDD cases and 1445 controls were involved in this meta-analysis. Overall, no significant association with MDD risk was provided in the Chinese population (C vs. T: OR=0.97, 95% CI: 0.81-1.17, 95%; CC vs. TT: OR=0.95, 95% CI: 0.65-1.37; CC+TC vs. TT: OR=0.96, 95% CI: 0.75-1.12; CC vs. TT+TC: OR=0.94, 95% CI: 0.78-1.12). In subgroup analyses stratified by geographic area and source of controls, no significant association was found in any of the subgroups. In conclusion, this meta-analysis indicate that the HTR2A T102C polymorphism is not associated with susceptibility to MDD in Chinese population.
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UNC-51 like kinase (ULK1) translocates to dysfunctional mitochondria and is involved in mitophagy, but the mechanisms responsible for ULK1 activation and translocation remain unclear. Here, we found that hypoxia induces phosphorylation of ULK1 at Serine-555 by Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Unlike wild-type ULK1, an ULK1 (S555A) mutant cannot translocate to mitochondria in response to hypoxia. Inhibition or knockdown of AMPK prevents ULK1 translocation and inhibits mitophagy. Finally, the phospho-mimic ULK1 (S555D) mutant, but not ULK1 (S555A), rescues mitophagy in AMPK-knockdown cells. Thus, we conclude that AMPK-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress.