Hsa_circ_0001944 enhanced GSPT1 expression via sponging miR-498 to promote proliferation and invasion of gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide. CircRNAs may provide new insights into the development of GC by acting as oncogenes or tumor suppressors. In this study, we aim to examine the biological role of hsa_circ_0001944 (circFIRRE) in tumor progression of GC. METHODS: The bioinformatic analysis, qPCR, Western blotting, and immunohistochemistry were fulfilled to detect the expression of hsa_circ_0001944, miR-498, and GSPT1 in gastric cancer. Gain or loss of function approaches were used to investigate the biological functions of hsa_circ_0001944. MTS, EDU, wound healing, and transwell assays were performed to study the proliferation, invasion, and migration of GC cells. These molecular mechanisms were detected by luciferase reporter assays and chromatin immunoprecipitation assays. RESULTS: We screened out hsa_circ_0001944, whose expression was significantly increased in gastric cancer tissues. Knockdown of hsa_circ_0001944 significantly suppressed the cell proliferation, invasion, and migration. Mechanistic investigations showed that hsa_circ_0001944 can bind to and sponge miR-498. Moreover, hsa_circ_0001944 sponged miR-498 to increase GSPT1 expression, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells. CONCLUSION: The present study demonstrates the hsa_circ_0001944/miR-498/GSPT1 axis contributes to GC development. This may provide a target for GC therapy and potential prognostic biomarker.

High expression of COX5B is associated with poor prognosis in breast cancer.

BACKGROUND: Cytochrome c oxidase subunit VB (COX5B), a subunit of mammalian COX, takes roles in COX assembling and functions. Online database predicts high COX5B transcription may be associated with worse disease-free survival (DFS). However, the clinical implications of COX5B in breast cancer remain unclear. METHODS: We carried out immunohistochemistry on tissue microarrays of 244 patients with invasive ductal breast carcinoma to detected COX5B expression. RESULTS: Our results suggest that COX5B protein level might be associated with tumor size. COX5B overexpression indicated a worse DFS (p < 0.05) in breast cancer. Furthermore, high COX5B expression may act as an independent factor for worse DFS in breast cancer. CONCLUSIONS: Cumulatively, our findings suggest that COX5B might serve as an important prognostic factor for breast cancer.

Loss of TIM50 suppresses proliferation and induces apoptosis in breast cancer.

TIM50 is an essential component of TIM23 complex and involved in protein translocating into the inner mitochondrial membrane. Here, we found that TIM50 was increased in breast cancer cells by SILAC. However, its biological functions and molecular mechanisms in breast cancer are poorly understood. To gain insight into the functions of TIM50 in breast cancer, we constructed two stably transfected cell lines and examined TIM50 expression in tissue samples. Our data showed that TIM50 expression was increased in breast cancer. The stable suppression of TIM50 expression through lentivirus-mediated shRNA was shown to inhibit the abilities of cancer cell proliferation and induce apoptosis. What is more, depletion of TIM50 could decrease mitochondrial membrane potential, which may be associated with cell viability. Taken together, our findings reveal a new role for TIM50 in regulating cell proliferation and apoptosis through decreasing mitochondrial membrane potential in breast cancer cell and suggest that TIM50 might be a potential target for controlling breast cancer progression.

Nrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene.

BRCA1 is closely related to the pathogenesis of breast cancer. The activity of BRCA1 promoter is regulated by transcriptional factors. The transcription factor Nrf2 (Nuclear factor-erythroid-2p45-related factor 2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes. In this report, we found that over-expression of Nrf2 stimulated BRCA1 expression, knockdown of Nrf2 attenuated BRCA1 expression. Nrf2 also interacted with CBP and p300 to form an active transcription complex, which could bind to the ARE (antioxidant response element) site on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Our finding could lead to a better understanding of the development of breast cancer.

Phase I study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours.

In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody-drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard "3 + 3" design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors.

BACKGROUND: Pucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period. RESULTS: A total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1-23.5 days across all dose groups. CONCLUSIONS: Pucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.

SNHG22 overexpression indicates poor prognosis and induces chemotherapy resistance via the miR-2467/Gal-1 signaling pathway in epithelial ovarian carcinoma.

Recently, an increasing number of studies have reported that dysregulation of long noncoding RNAs (lncRNAs) plays an important role in cancer initiation and progression, including in epithelial ovarian carcinoma (EOC). However, little is known about the detailed biological functions of the lncRNA small nucleolar RNA host gene 22 (SNHG22) during the progression of EOC. Here, we found that SNHG22 was significantly increased in EOC tissues and was significantly associated with a low level of differentiation. Forced SNHG22 expression promoted chemotherapy resistance in EOC cells. Knockdown of SNHG22 expression increased the sensitivity of EOC cells to cisplatin and paclitaxel. Importantly, we found that SNHG22 could directly interact with miR-2467 and lead to the release of miR-2467-targeted Gal-1 mRNA. Moreover, SNHG22 overexpression induced EOC cell resistance to chemotherapy agents via PI3K/AKT and ERK cascade activation. In summary, our findings demonstrate that SNHG22 plays a critical role in the chemotherapy resistance of EOC by mediating the miR-2467/Gal-1 regulatory axis.

Downregulation of FOXP2 promotes breast cancer migration and invasion through TGFß/SMAD signaling pathway.

Cancer metastasis and relapse are the primary cause of mortality for patients with breast cancer. The present study performed quantitative proteomic analysis on the differentially expressed proteins between highly metastatic breast cancer cells and parental cells. It was revealed that forkhead box P2 (FOXP2), a transcription factor in neural development, may become a potential inhibitor of breast cancer metastasis. The results demonstrated that patients with a lower level of FOXP2 expression had significantly poorer relapse-free survival (P=0.0047). The transcription of FOXP2 was also significantly downregulated in breast cancer tissue compared with normal breast tissue (P=0.0005). In addition, FOXP2 may inhibit breast cancer cell migration and invasion in vitro. It was also revealed that the underlying mechanism may include the epithelial-mesenchymal transition process driven by the tumor growth factor ß/SMAD signaling pathway. In conclusion, the present study identified FOXP2 as a novel suppressor and prognostic marker of breast cancer metastasis. These results may provide further insight into breast cancer prevention and the development of novel treatments.

Trends and outcomes of neoadjuvant radiotherapy compared with postoperative radiotherapy for malignant breast cancer.

BACKGROUND: Although neoadjuvant treatment has become the established approach for women with large primary tumors or locally advanced breast cancer for which immediate surgery is not the best approach, it may also stimulate cancer stem cell self-renewal and facilitate recurrence. We sought to determine the survival outcomes of preoperative radiotherapy (PRRT) compared with postoperative radiotherapy (PORT). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients who were diagnosed with breast cancer and underwent cancer-directed surgery. Survival analyses were performed with Cox proportional hazard regression for both overall survival (OS) and disease-specific survival (DSS), and 1:1 propensity score (PS) matching-adjusted competing risk analyses were conducted for DSS. RESULTS: We first identified 1,111,218 eligible patients in 18 registries from 1973 to 2013 and found that, outside of the Utah registry, sequence patterns other than PORT were rarely used. Thus, we next identified eligible patients registered in Utah (n = 7,042) from 1988 to 2007. The treatment trends shifted abruptly in 1988. Compared with the PORT group, the PRRT group showed significantly higher risks of overall mortality (absolute difference, 22.4%; P < 0.001), breast cancer-specific mortality (absolute difference, 8.6%; P < 0.001), and cardiovascular disease-specific mortality (absolute difference, 11.5%; P = 0.021). Survival differences in treatment sequences were correlated with stage. CONCLUSIONS: Substantial shifts in treatment patterns for malignant breast cancer were identified in Utah. Compared with PORT, PRRT showed significantly worse outcomes. These results could inform future standardized options for radiation sequence with surgery and further clinical trials.

Clinicopathological characteristics and survival outcomes in Paget disease: a SEER population-based study.

The objective of this study was to investigate the clinicopathological characteristics and survival outcomes of Paget disease (PD), Paget disease concomitant infiltrating duct carcinoma (PD-IDC), and Paget disease concomitant intraductal carcinoma (PD-DCIS). We identified 501,631 female patients from 2000 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database. These identified patients included patients with PD (n = 469), patients with PD-IDC (n = 1832), and patients with PD-DCIS (n = 1130) and infiltrating ductal carcinoma (IDC) (n = 498,076). Then, we compared the clinical characteristics of these patients with those who were diagnosed with IDC during the same period. The outcomes of these subtypes of breast carcinoma were different. Based on the overall survival, the patients with PD-IDC had the worst prognosis (5-year survival rate = 84.1%). The PD-DCIS had the best prognosis (5-year survival rate = 97.5%). Besides, among patients with Paget disease, the one who was married had a better prognosis than who were not. And, according to our research, the marital status was associated with the hormone receptor status in patients with PD-IDC. Among three subtypes of Paget disease, patients with PD-IDC had the worst prognosis. Besides, patients who were unmarried had worse outcomes. And the marital status of patients with PD-IDC is associated with hormone status. The observation underscores the importance of individualized treatment.

UHRF1 promotes breast cancer progression by suppressing KLF17 expression by hypermethylating its promoter.

UHRF1 is an epigenetic regulator and perform pivotal functions in cell tumorigenesis. We found UHRF1 is increased in breast cancer and patients with high UHRF1 levels have poorer prognoses than those with low UHRF1 levels. However, the underlying mechanisms remain largely unknown. Here, we found overexpression UHRF1 indeed promoted cell proliferation and migration, whereas its downregulation had the opposite functions. In vivo, UHRF1 also accelerated tumor growth. Mechanistically, microarrays were performed in MDA-MB-231 sh-UHRF1 and NC cells and KLF17, with rich CpG islands on its promoter region, finally caused our attention. Then, the expression of UHRF1 and KLF17 was testified negatively correlated in breast cancer cell lines and tissues. Additionally, the inhibition of cell proliferation and migration by UHRF1 depletion can be rescued by KLF17 silencing, suggesting KLF17 is downstream gene of UHRF1. The potential mechanism is that overexpression UHRF1 increased methylation of CpG nucleotides on KLF17 promoter, while UHRF1 silence decreased methylation. Collectively, our results demonstrated that increased UHRF1 can promote breast cancer cell proliferation and migration via silencing of KLF17 expression through CpG island methylation on its promoter.

Comparison of patterns and prognosis among distant metastatic breast cancer patients by age groups: a SEER population-based analysis.

To investigate the effects of age at diagnosis on metastatic breast cancer and patients' prognosis, we collected patient data from the Surveillance, Epidemiology, and End Results (SEER) database. We finally identified 4932 eligible metastatic breast cancer patients diagnosed between 2010-2013, including 850 younger patients (<50 years), 2,540 middle-aged patients (50-69 years) and 1,542 elder patients (>69 years). The results revealed that in stage IV patients, elder patients were more likely to have lung metastasis (P < 0.001) and less likely to have only distant lymphatic spread (P = 0.004). Higher proportion of younger (34.9%) and middle-aged (36.2%) patients had multiple metastatic sites than elder patients (28.3%) (P < 0.001). In survival analysis, younger patients presented the best prognosis, while elder patients had the worst both in overall survival (χ2 = 121.9, P < 0.001) and breast cancer-specific survival (χ2 = 69.8, P < 0.001). Age at diagnosis was an independent prognostic factor for metastatic breast cancer patients. Moreover, patients with bone metastasis only had superior survival compared to other metastatic patients (P < 0.001). Brain metastasis only group and multiple sites metastasis group had the poorest prognosis (P < 0.05). We hope the results will provide insights into a better understanding of distant metastatic breast cancer.

Clinicopathological characteristics and survival outcomes of male breast cancer according to race: A SEER population-based study.

To investigate the clinicopathological characteristics and survival outcomes of breast cancer in the male population, 8,607 cases of patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database, including white males (n = 7122), black males (n = 1111), and other males (American Indian/AK Native, Asian/Pacific Islander) (n = 374). Black male breast cancer patients were more likely to be in stages II-IV and have more advanced tumors. The rate of lymph node (LN) involvement at diagnosis was higher in black men than in whites and others. The ER- and PR-positive rates were lower in black men than in whites and others. The distant metastasis rate was higher in blacks than in whites and others. Furthermore, the overall survival (OR) rates and breast cancer-specific survival rates were significantly poorer in blacks than in whites and others (χ2 = 29.974, P < 0.001; χ2 = 7.285, P = 0.026, respectively). In a multivariate analysis, the results showed that race could also be a prognostic indicator (P < 0.001). Moreover, significant differences were also observed in OS among 1:1:1 matched white, black, and other groups (P < 0.001). Differences in outcomes may be partially explained by differences in tumor grades, LN status, and ER and PR status between the 3 groups. This study might provide insights into a better understanding of male breast cancer.

SSBP1 Suppresses TGFß-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling.

Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is, therefore, an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify mitochondrial proteins involved in TNBC metastasis. We found that single-strand DNA-binding protein 1 (SSBP1) was downregulated in highly metastatic breast cancer cells. Moreover, SSBP1 downregulation promoted TNBC cell metastasis in vitro and in vivo. Mechanistically, SSBP1 loss decreased mitochondrial DNA copy number, thereby potentiating calcineurin-mediated mitochondrial retrograde signaling that induced c-Rel/p50 nuclear localization, activated TGFß promoter activity, and TGFß-driven epithelial-to-mesenchymal transition. Low SSBP1 expression correlated with tumor progression and poor prognosis in patients. Collectively, our findings identified SSBP1 as a novel metastasis suppressor and elucidated the mechanisms by which dysregulated mitochondrial signaling contributes to metastatic potential, providing potential new prognostic indicators for patients with TNBC.

Down-Regulation of NDUFB9 Promotes Breast Cancer Cell Proliferation, Metastasis by Mediating Mitochondrial Metabolism.

Despite advances in basic and clinical research, metastasis remains the leading cause of death in breast cancer patients. Genetic abnormalities in mitochondria, including mutations affecting complex I and oxidative phosphorylation, are found in breast cancers and might facilitate metastasis. Genes encoding complex I components have significant breast cancer prognostic value. In this study, we used quantitative proteomic analyses to compare a highly metastatic cancer cell line and a parental breast cancer cell line; and observed that NDUFB9, an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I), was down-regulated in highly metastatic breast cancer cells. Furthermore, we demonstrated that loss of NDUFB9 promotes MDA-MB-231 cells proliferation, migration, and invasion because of elevated levels of mtROS, disturbance of the NAD+/NADH balance, and depletion of mtDNA. We also showed that, the Akt/mTOR/p70S6K signaling pathway and EMT might be involved in this mechanism. Thus, our findings contribute novel data to support the hypothesis that misregulation of mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, suggesting that complex I deficiency is a potential and important biomarker for further basic research or clinical application.

Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer.

COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Down-regulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.

Loss of RAB1B promotes triple-negative breast cancer metastasis by activating TGF-ß/SMAD signaling.

Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype associated with a poor prognosis. The mechanism involved in TNBC progression remains largely unknown. To date, there are no effective therapeutic targets for this tumor subtype. In this study, by performing quantitative proteomic analyses in highly metastatic and parental breast cancer cell line, we found that RAB1B, a member of the RAS oncogene family, was significantly down-regulated in highly metastatic breast cancer cells. Moreover, down-regulation of RAB1B was also found to promote the proliferation and migration of TNBC cells in vitro and in vivo. Mechanistically, loss of RAB1B resulted in elevated expression of TGF-ß receptor 1 (TßR1) through decreased degradation of ubiquitin, increased levels of phosphorylated SMAD3 and TGF-ß-induced epithelial-mesenchymal transition (EMT). Furthermore, low RAB1B expression correlated with poor prognosis in breast cancer patients. Taken together, our findings reveal that RAB1B acts as a metastasis suppressor in TNBC by regulating the TGF-ß/SMAD signaling pathway and RAB1B may serve as a novel biomarker of prognosis and the response to anti-tumor therapeutics for patients with TNBC.