Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway.

BACKGROUND: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.

The role of postoperative radiotherapy (PORT) in lymphoepithelial carcinoma of the salivary gland (LECSG) and the effect of postoperative EBV DNA on prognosis.

BACKGROUND: Whether postoperative radiotherapy (PORT) could improve survival and the role of EBV DNA remains unclear for patients with lymphoepithelial carcinoma of the salivary glands (LECSG). PATIENTS AND METHODS: 360 patients were included. Independent prognostic factors were selected using a Cox proportional hazards model and incorporated into risk stratification. RESULTS: The number of positive lymph nodes (PLNs) ≥ 3 and tumor size ≥ 3 cm were independent factors for PFS in patients with neck dissection (ND). Patients were divided into three groups: high-risk, size ≥ 3 cm&PLNs ≥ 3; intermediate-risk, size < 3 cm&PLNs ≥ 3 or size ≥ 3 cm&PLNs < 3; low-risk, size < 3 cm&PLNs < 3. The 5-year PFS rate of the low-, intermediate- and high-risk patients receiving non-PORT and PORT was 87.9% vs 93.5% (p = 0.12), 41.2% vs 81.1% (p < 0.001), 18.0% vs 51.1% (p = 0.034). N stage was an independent factor for PFS in patients with non-neck dissection (NND) and patients were divided into two groups: low-risk, N0; and high-risk, N1/2. The 5-year PFS rate of the low-risk, and high-risk patients receiving non-PORT and PORT was 77.9% vs 94.3% (p = 0.0019), 21.4% vs 71.3% (p = 0.015). Compared with EBV DNA = 0, the 5-year PFS rate of patients with EBV DNA > 0 was 19.9% vs 91.3% (p < 0.001). In patients with EBV DNA = 0, the 5-year PFS rate of patients with or without PORT was 95.1% vs 92.3% (p = 0.082); while in patients with EBV DNA > 0, the 5-year PFS rate was 37% vs 9.2% (p = 0.0056). CONCLUSIONS: In patients with ND, PLNs < 3&size < 3 cm patients did not benefit from PORT. Detectable EBV DNA after surgery was a negative prognostic factor.

Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer.

Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Radiation-induced lymphopenia and the survival of women with cervical cancer: a meta-analysis.

The current systematic analysis and meta-analysis was aimed to evaluate the association between radiation-induced lymphopenia (RIL) and survival of women with cervical cancer (CC). PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant cohort studies comparing survival between women with CC who developed versus not developed RIL after radiotherapy. We pooled the results using a random-effects model that incorporates heterogeneity. In the meta-analysis, 952 women with CC were included from eight cohort studies. Overall, 378 (39.7%) of them had RIL after radiotherapy. During a median follow-up duration of 41.8 months, pooled results showed that RIL was independently associated with poor overall survival (hazard ratio [HR]: 2.67, 95% confidence interval [CI]: 1.81 to 3.94, p < 0.001; I2 = 20%) and progression-free survival (HR: 2.17, 95% CI: 1.58 to 2.98, p < 0.001; I2 = 0%). Predefined subgroup analyses showed similar results in patients with grade 3-4 and grade 4 RIL, in patients with RIL diagnosed during or after the radiotherapy, and in studies with quality score of seven or eight points (p values for subgroup effect all < 0.05). In conclusion, women with RIL were associated with poor survival after radiotherapy for CC.

Role of brachytherapy in post-operative cervical cancer patients with risk factors other than positive stump.

OBJECTIVE: This study aimed to determine the effectiveness of brachytherapy in post-operative cervical cancer patients with risk factors other than positive stump, and to identify the candidates most likely to benefit. METHODS: Newly diagnosed, non-metastatic cervical cancer patients treated in our hospital between January 2012 and November 2015 were retrospectively reviewed. Early stage patients receiving radical surgery and needing adjuvant external radiotherapy were included, but those with positive stump were excluded. All patients received external radiotherapy. They were divided into two groups: one group received vaginal brachytherapy and the other did not. The 5-year local-regional recurrence free survival (LRRFS) and overall survival (OS) rates in the two groups were compared. RESULTS: Two hundred and twenty-five patients were included in this study; while 99 received brachytherapy, 126 did not. The brachytherapy group had significantly superior 5-year LRRFS (87.7% vs. 72.5%, p = 0.004), but did not show a significant overall survival benefit (78.4% vs. 75.3%, p = 0.055). In multivariate analysis, brachytherapy, pathological type, high-risk factors, duration of radiotherapy, and transfusion were independent prognostic factors for 5-year LRRFS. In stratified analysis, the brachytherapy group showed superior LRRFS in those meeting Sedlis criteria (p = 0.017). CONCLUSION: The combination of external beam radiation therapy and brachytherapy can improve LRRFS in post-operative cervical cancer patients with risk factors other than positive stump. Therefore, brachytherapy should be considered for these patients.

Contouring the accessory parotid gland and major parotid glands as a single organ at risk during nasopharyngeal carcinoma radiotherapy.

Background and purpose: No research currently exists on the role of the accessory parotid gland (APG) in nasopharyngeal carcinoma (NPC). We thereby aimed to assess the effects of APG on the dosimetry of the parotid glands (PGs) during NPC radiotherapy and evaluate its predictive value for late xerostomia. Material and methods: The clinical data of 32 NPC patients with radiological evidence of the APG treated at Sun Yat-sen Memorial Hospital between November 2020 and February 2021 were retrospectively reviewed. Clinically approved treatment plans consisted of only the PGs as an organ at risk (OAR) (Plan1), while Plan2 was designed by considering the APG as a single organ at risk (OAR). The APG on Plan1 was delineated, and dose-volume parameters of the PGs alone (PG-only) and of the combined structure (PG+APG) were analyzed in both plans. The association of such dosimetric parameters in Plan1 with xerostomia at 6-9 months post-radiotherapy was further explored. Results: Fifty APGs were found, with a mean volume of 3.3 ± 0.2 ml. Significant differences were found in all dosimetric parameters between Plan1 and Plan2. The mean dose and percentage of OAR volumes receiving more than 30 Gy significantly reduced in Plan1 itself (PG-only vs. PG+APG, 39.55 ± 0.83 Gy vs. 37.71 ± 0.75 Gy, and 62.00 ± 2.00% vs. 57.41 ± 1.56%, respectively; p < 001) and reduced further in Plan2 (PG+APG, 36.40 ± 0.74 Gy, and 55.54 ± 1.61%, respectively; p < 0.001). Three additional patients met the dose constraint in Plan1, which increased to seven in Plan2. With APG included, the predictive power of the dosimetric parameters for xerostomia tended to improve, although no significant differences were observed. Conclusion: APG is anatomically similar to the PGs. Our findings suggest the potential benefits of treating the APG and PGs as a single OAR during radiotherapy (RT) of NPC by improving PG sparing.

Enhanced Efficacy of Neoadjuvant Chemotherapy with Nab-Paclitaxel and Platinum for Locally Advanced Cervical Cancer.

PURPOSE: We aimed to determine the effect of neoadjuvant chemotherapy consisting of albumin-bound paclitaxel ("nab-paclitaxel") and platinum (NACT-nPP) in patients with locally advanced cervical cancer (LACC). METHODS: Consecutive patients with newly diagnosed, non-metastatic LACC were recruited retrospectively between October 2016 and June 2020 in our hospital. All patients received concurrent chemoradiotherapy (CCRT) alone or neoadjuvant chemotherapy. We compared the complete response (CR) rate and 2-year progression-free survival (PFS) between patients receiving NACT-nPP and not receiving regimens or other regimens of neoadjuvant chemotherapy. RESULTS: A total of 195 patients were enrolled (78 in the NACT-nPP group and 117 in the control group). Upon chemoradiotherapy completion, 72 (92.3%) patients in the NACT-nPP group and 96 (82.1%) patients in the other group achieved CR (P = 0.042). For patients with squamous cell carcinoma, the NACT-nPP group had superior 2-year PFS than that of the control group (89.7% vs 74.1%, P = 0.027, HR = 2.486, 95% CI = 1.077-5.739) whereas for adenocarcinoma, 2-year PFS was 37.5% and 36.5%, respectively (P = 0.863). In multivariate analysis, NACT-nPP and stage were independent prognostic factors (P = 0.046 and 0.012, HR = 2.357 and 2.499, 95% CI = 1.016-5.465 and 1.216-4.930, respectively). The acute hematological adverse events above grade 3 were manageable in the NACT-nPP group (46.2%, 36/78), and the rate was lower than that in the control group (55.6%, 65/117). CONCLUSION: Compared with CCRT alone, NACT-nPP followed by CCRT could improve the CR rate and 2-year PFS of patients with locally advanced cervical squamous cell carcinoma, and the toxicity was tolerable. NACT-nPP was an independent prognostic factor for 2-year PFS. However, further prospective studies are needed to confirm our results.

Brachytherapy-based radiotherapy is associated with improved survival for newly diagnosed metastatic cervical cancer.

PURPOSE: The purpose of this study was to explore the value of brachytherapy (BT) in metastatic cervical cancer, as it has not been well evaluated before. METHODS AND MATERIALS: We analyzed 2391 patients with Stage IVB cervical cancer from 2004 to 2015 by using data from the Surveillance, Epidemiology, and End Results registry. The parameters were analyzed by Kaplan-Meier and Cox proportional hazards regression models to evaluate cancer-specific survival (CSS) and overall survival. RESULTS: In general, both univariate and multivariate analysis showed that age, histologic type, tumor size, and chemotherapy were associated with CSS and overall survival (p < 0.05). Further subgroup analysis showed BT alone or BT combined with external beam radiotherapy improved CSS despite the tumor size. In addition, chemotherapy and chemoradiotherapy prolonged CSS compared with external beam radiotherapy alone or no chemotherapy or radiotherapy independently of tumor size (p < 0.05). CONCLUSIONS: For newly diagnosed metastatic cervical cancers, BT with or without external beam radiotherapy is associated with improved survival. As an aggressive option, chemoradiotherapy is also a potential treatment strategy.

[Corrigendum] The specific killing effect of matrine on castration­resistant prostate cancer cells by targeting the Akt/FoxO3a signaling pathway.

Subsequently to the publication of the article, the authors have realized that some errors were contained therein that went uncorrected before the paper was sent to press. First, Fig. 4 contained a pair of data panels that had been misplaced: The LY294002, PC­3 data panel in Fig. 4A showed the same data as the RWPE­1, control panel in Fig. 4B, and the LY294002, RWPE­1 data panel showed the same data as the matrine, control panel in Fig. 4B. These errors arose inadvertently during the process of re­organizing the layout of the figure; a corrected version of Fig. 4, showing the correct data panels for the LY294002, PC­3 and LY294002, RWPE­1 experiments in Fig. 4A and B respectively, is shown on the next page. Also note that the data shown in Fig. 4C and E have been re­calculated on the basis of the correction of the data in this Figure, and the revised histograms are also shown in these Figure parts. In view of these corrections, in the "Matrine induces cell apoptosis by increasing Bim and Bax and decreasing Bcl­2 protein levels in prostate cancer cell lines" subsection of the Results section towards the bottom of p. 2822, in the penultimate sentence, the text "...LY294002 resulted in 25.88% cell apoptosis in the PC­3 cells and 18.88% in the RWPE1 cells, compared to 3.11 and 6.89%, respectively, with LY294002 treatment only (Fig. 4A­D)." should be corrected to: "...LY294002 resulted in 25.88% cell apoptosis in the PC­3 cells and 18.88% in the RWPE1 cells, compared to 10.94% and 6.89%, respectively, with LY294002 treatment only (Fig. 4A­D)." (the changed datum is shown in bold). Note that the corrected data shown in Fig. 4, and the revision made to the Results section, do not affect the overall conclusions reported in the paper. The authors thank the Editor of Oncology Reports for allowing them the opportunity to present this Corrigendum, and apologize and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 37: 2819-2828, 2017; DOI: 10.3892/or.2017.5510].

Overexpression of malignant brain tumor domain containing protein 1 predicts a poor prognosis of prostate cancer.

Malignant brain tumor domain containing protein 1 (MBTD1) is a member of the polycomb group protein family that is associated with tumorigenesis. The present study investigated the role of MBTD1 within defined clinicopathological parameters and the prognosis of patients with prostate cancer (PCa). A human tissue microarray containing samples from 71 patients with PCa and seven healthy donors was employed for immunohistochemistry (IHC). The clinicopathological characteristics and prognostic value of MBTD1 were investigated using a dataset of 499 patients from The Cancer Genome Atlas (TCGA). IHC illustrated that the levels of MBTD1 protein were enhanced and markedly associated with aggressive clinical stage and advanced tumor invasion, distant metastasis and lymph node metastasis in patients with PCa. In the TCGA data set, the level of MBTD1 was found to positively correlate with the prostate-specific antigen level, Gleason score and distant metastasis. The multivariate analysis of Cox regression revealed that the levels of MBTD1 may act as an independent prognostic factor for low non-biochemical, recurrence-free survival. In conclusion, MBTD1 was overexpressed in PCa tissues and is associated with aggressive clinicopathological characteristics. It may therefore act as a novel prognostic factor and diagnostic marker in PCa.

Polo-like kinase 3 is associated with poor prognosis and regulates proliferation and metastasis in prostate cancer.

BACKGROUND: Biological mechanism of prostate cancer (PCa) recurrence and progress is complex but many of the key elements are not fully understood. Polo-like kinases (Plks) represent a family of highly conserved serine-threonine kinases that play essential roles in cell cycle progression. Plk3 plays contradictory roles in different cancers. However, the roles of Plk3 in PCa remain largely unexplored. METHODS: Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the relationship between Plk3 and prognosis of patients with PCa. Gene set enrichment analysis (GSEA) was conducted to evaluate proliferation and metastasis gene sets using The Cancer Genome Atlas Dataset. MTS assay, clone formation assay, cell migration, and wound healing assay were carried out to investigate biological functions of Plk3. RESULTS: We found that high Plk3 expression was closely correlated with poor prognosis. GSEA revealed that Plk3 was involved in proliferation and metastasis. Loss-of-function assays demonstrated that Plk3 promoted proliferation and metastasis in PCa cells in vitro. CONCLUSION: We discovered that Plk3 plays a critical role in PCa, indicating that it may be a potential prognostic marker and help predict the progression, especially recurrence of PCa.

Comparison of Significant Carotid Stenosis for Nasopharyngeal Carcinoma between Intensity-Modulated Radiotherapy and Conventional Two-Dimensional Radiotherapy.

Radiotherapy (RT) serves as the most efficient treatment for nasopharyngeal carcinoma (NPC) and can cause carotid stenosis. This work compared the incidence of significant carotid stenosis between intensity-modulated radiotherapy (IMRT) and two-dimensional conventional radiotherapy (2D-RT) for NPC and explored the risk factors. We retrospectively reviewed 233 cases with NPC who underwent carotid ultrasound post IMRT or 2D-RT from 2006 to 2015. The incidence of significant stenosis after RT was 19.3%. Significant stenosis was identified in 20 (14.6%) of 137 patients treated with IMRT and 25 (26.0%) of 96 patients with 2D-RT, respectively (p = 0.035). Multivariate logistic analysis indicated age (odds ratio = 1.054, 95% CI = 1.011-1.099, p = 0.014), radiation technique (IMRT) (odds ratio = 0.471, 95%CI = 0.241-0.919, p = 0.027) and time interval (odds ratio = 1.068, 95%CI = 1.033-1.105, p = 0.001) as independent predictors for significant carotid stenosis. Our study suggests that IMRT was associated with decreased incidence of significant carotid stenosis versus 2D-RT for NPC. Prevention and carotid ultrasound should be considered for older NPC survivors with longer interval from RT, especially those treated with 2D-RT.

Grafted Neural Stem Cells Show Lesion-Specific Migration in Radiation-Injured Rat Brains.

Neural stem cells (NSCs) exhibit preferential homing toward some types of brain lesion, but their migratory property during radiation brain injury (RBI) remains unexplored. Here, we use the superparamagnetic iron oxide (SPIO)-labeled magnetic resonance imaging (MRI) technology to determine the migration of transplanted NSCs in two partial RBI models in real time, created by administering 30-55 Gy of radiation to the right or posterior half of the adult rat brain. SPIO-labeled NSCs were stereotactically grafted into the uninjured side one week after RBI. The migration of SPIO-labeled NSCs in live radiation-injured brains was traced by MRI for up to 28 days after engraftment and quantified for their moving distances and speeds. A high labeling efficiency (>90%) was achieved by incubating NSCs with 100µg/ml of SPIO for 12-24 hours. Upon stereotactic transplantation into the healthy side of the brain, SPIO-labeled NSCs were distinctively detected as hypointense signals on T2-weighted images (T2WI), showed sustained survival for up to 4 weeks, and exhibited directional migration to the radiation-injured side of the brain with a speed of 86-127 µm/day. The moving kinetics of grafted NSCs displayed no difference in brains receiving a high (55 Gy) vs. moderate (45 Gy) dose of radiation, but was slower in the right RBI model than in the posterior RBI model. This study shows that NSCs can be effectively labeled by SPIO and traced in vivo by MRI, and that grafted NSCs exhibit directional migration toward RBI sites in a route-dependent but radiation dose-independent manner.

Excessive Pretreatment Weight Loss Is a Risk Factor for the Survival Outcome of Esophageal Carcinoma Patients Undergoing Radical Surgery and Postoperative Adjuvant Chemotherapy.

Background: The prognostic values of weight loss and body mass index (BMI) in esophageal carcinoma remain controversial. This study aimed to evaluate the impacts of weight loss on the survival of patients undergoing radical surgery and adjuvant chemotherapy. Methods: The medical records of 189 consecutive patients with nonmetastatic esophageal carcinoma treated in our hospital between January 2012 and December 2013 were reviewed, and 121 patients were included for analysis. Results: Kaplan-Meier analysis revealed that the 3-year overall survival rate was significantly higher in the low pretreatment weight loss (pre-LWL) group than in the high pretreatment weight loss (pre-HWL) group (P < 0.001). In addition, the 3-year overall survival rate of normal weight group was higher than that of overweight and underweight groups (P = 0.007). Multivariate Cox proportional hazards analysis showed that pre-LWL group had a significantly better 3-year overall survival than pre-HWL group (P = 0.027, HR = 1.89, and 95% CI = 1.07-3.32). pN stage and age were also the survival prognostic factors. Conclusions: Our study showed that low pretreatment weight loss predicted a better survival outcome in the esophageal carcinoma patients with radical surgery and adjuvant chemotherapy. However, BMI and weight loss during treatment had no impact on the survival outcome.

High levels of DEPDC1B predict shorter biochemical recurrence-free survival of patients with prostate cancer.

DEP domain-containing protein 1B (DEPDC1B) has been reported to serve important functions in breast cancer and non-small cell lung cancer. However, its involvement in the development of prostate cancer (PCa) remains unclear. Therefore, the present study aimed to investigate the expression and clinical significance of DEPDC1B in tumor tissues from patients diagnosed with PCa. A total of 80 prostate tissue samples were collected following prostatectomy to generate a tissue microarray for immunohistochemical analysis of DEPDC1B protein expression. High throughput sequencing of mRNAs from 179 prostate tissue samples, either from patients with PCa or from healthy controls, was included in the Taylor dataset. The expression levels of DEPDC1B in tumor tissues from patients with PCa were revealed to be significantly increased compared with those in normal prostate tissues (P=0.039). Increased expression of DEPDC1B was significantly associated with advanced clinical stage (P=0.006), advanced T stage (P=0.012) and lymph node metastasis (P=0.004). Kaplan-Meier analysis demonstrated that patients with high levels of DEPDC1B mRNA had significantly shorter biochemical recurrence (BCR)-free survival times. Multivariate analysis using Cox proportional hazards model revealed that levels of DEPDC1B mRNA were significant independent predictors of BCR-free survival time of patients with PCa. Therefore, the expression of DEPDC1B may be used as an independent predictor of biochemical recurrence-free survival time of patients with PCa.

The specific killing effect of matrine on castration-resistant prostate cancer cells by targeting the Akt/FoxO3a signaling pathway.

Matrine, a Sophora alkaloid, exhibits antiproliferative and anti-carcinogenic activities through several mechanisms. In a previous study, we found that matrine could effectively inhibit the proliferation of castration-resistant prostate cancer (CRPC). In the present study, the effect of matrine and LY294002 on the expression of the Akt/FoxO3a signaling pathway was examined by western blot analyses and RT-PCR. We discovered that matrine significantly inhibited the proliferation of both prostate cancer cell line PC-3 and prostate epithelial cell line RWPE1, induced apoptosis and induced cell cycle arrest. In addition, LY294002 was found to enhance the effect of matrine. Furthermore, the effects of matrine on the inhibition of proliferation and the induction of cell cycle arrest and cell apoptosis were more effective on PC-3 than on RWPE1 cells. Compared to RWPE1 cells, matrine exerted a more powerful influence on PC-3 cells in increasing the expression of the relevant protein. Our data suggested that FoxO3a-Bim and FoxO3a-P27 may mediate matrine-inhibited proliferation of CRPC cells by activating cell apoptosis and inducing cell cycle arrest. Matrine exhibited high selectivity in killing CRPC cells. Our findings demonstrated that matrine could be used in a potential therapeutic role in the management of CRPC in humans.

RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.

INTRODUCTION: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown. EXPERIMENTAL DESIGN: We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models. RESULTS: We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment. CONCLUSIONS: Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514-22. ©2016 AACR.

Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells.

Increasing evidence suggests that lineage specific subpopulations and stem-like cells exist in normal and malignant breast tissues. Epigenetic mechanisms maintaining this hierarchical homeostasis remain to be investigated. In this study, we found the level of microRNA221 (miR-221) was higher in stem-like and myoepithelial cells than in luminal cells isolated from normal and malignant breast tissue. In normal breast cells, over-expression of miR-221 generated more myoepithelial cells whereas knock-down of miR-221 increased luminal cells. Over-expression of miR-221 stimulated stem-like cells in luminal type of cancer and the miR-221 level was correlated with clinical outcome in breast cancer patients. Epithelial-mesenchymal transition (EMT) was induced by overexpression of miR-221 in normal and breast cancer cells. The EMT related gene ATXN1 was found to be a miR-221 target gene regulating breast cell hierarchy. In conclusion, we propose that miR-221 contributes to lineage homeostasis of normal and malignant breast epithelium.

Distinct prognostic values of ALDH1 isoenzymes in breast cancer.

Aldehyde dehydrogenase 1 (ALDH1), also known as aldehyde dehydrogenase 1 family, is composed of six enzymes that are expressed at high levels in stem cells and are involved in the regulation of stem cell function. Increased ALDH1 activity has been found in the stem cell populations of leukemia and some solid tumors including breast cancer (BC). However, which ALDH1's isoenzymes are contributing to ALDH1 activity has not been determined. In addition, the prognostic value of individual ALDH1 isoenzyme is not clear. In the current study, we investigated the prognostic value of ALDH1 isoenzymes in BC patients through "the Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information are from a total of 3455 BC patients. ALDH1A1 messenger RNA (mRNA) high expression was found to be correlated to worsen overall survival (OS) for all BC patients. ALDH1A2 and ALDH1L1 mRNA high expressions were found to be correlated to better OS for all BC patients. Both of ALDH1A3 and ALDH1B1 mRNA high expressions were not found to be correlated to OS for all BC patients. These results strongly support that ALDH1A1 was only a biomarker for predicting poor survival of BC patients among ALDH1 isoenzymes. ALDH1A1 might be a major contributor of ALDH1 activity in BC, since only ALDH1A1 mRNA high expression was found to be significantly correlated to worsen OS for all BC patients.