Recurrent Tuberous Sclerosis Complex​​​​​/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart.

ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 (TSC1, 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

Effect of neoadjuvant therapy on serum transforming growth factor-ß, squamous cell carcinoma associated antigen, and prognosis in patients with locally advanced esophageal cancer.

It was to explore the effect of neoadjuvant therapy (NAT) on serum-related indicators and prognosis of patients with locally advanced esophageal cancer (EC). 400 EC patients were grouped as controls (295 cases, radical EC resection alone) and research group (105 cases, NAT plus radical EC resection). The levels of serum carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), programmed death-1 (PD-1), PD-2, transforming growth factor-ß1 (TGF-ß1), and squamous cell carcinoma (SCC) antigen were detected before and after treatment. The follow-up lasted for 3 years. The quality of life (QoL) was evaluated by QLQ-OES24. The recurrence rate, recurrence time, overall survival rate (SR), disease-free SR, and complication rate were compared. Compared with controls, the levels of serum CA19-9, CEA, CYFRA21-1, PD-1, PD-2, TGF-ß1, and SCC were decreased, the QoL score was increased 3 years post-treatment, and the recurrence time was prolonged in the research group (P<0.05). The R0 resection rate, recurrence rate, 3-year overall SR, and disease-free SR of the two groups were 67.12% vs 85.71%, 21.36% vs 6.67%, 56.27% vs 77.14%, 29.83% vs 45.71%, respectively (P<0.05). The complication rates of the two groups were 32.54% and 29.52%, respectively (P>0.05). NAT plus radical resection of EC can effectively reduce the level of serum oncology markers in patients with locally advanced EC, reduce the postoperative recurrence rate, improve QoL and SR, and has high safety.

Clinicopathologic Features and Genomic Signature of De Novo CD5 + Diffuse Large B-Cell Lymphoma : A Multicenter Collaborative Study.

De novo CD5 + diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5 + DLBCL and 60 patients with CD5 - DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5 - DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5 + DLBCL. Most patients with CD5 + DLBCL had lymph nodes with non-germinal center B-cell-like or activated B-cell-like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88 and CD79B mutations) in the CD5 + DLBCL cohort was higher than that in the CD5 - DLBCL cohort (54.2% vs. 13.0%, P =0.005). Compared with the CD5 - cohort, CD5 + DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P <0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5 + DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5 + DLBCL patients. In summary, CD5 + DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell-like and MCD subtypes with worse survival outcome.

LPCAT1 reprogramming cholesterol metabolism promotes the progression of esophageal squamous cell carcinoma.

Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.

Enhanced Antitumor Efficacy of Macrophage-Mediated Egg Yolk Lipid-Derived Delivery System Against Breast Cancer.

BACKGROUND: Chemotherapy is the primary treatment for most cancers apart from surgery. However, the use of chemotherapeutic drugs is limited by side effects and restricted accumulation in tumors because of unique tumor microenvironments. Macrophages have excellent drug delivery potential owing to their chemotaxis and can home in on tumors. MATERIALS AND METHODS: We developed an effective drug-delivery system for doxorubicin using macrophages. Doxorubicin-loaded egg yolk lipid-derived nanovectors (EYLNs-Dox) were prepared, EYLNs-Dox-loaded macrophages (Mac/EYLNs-Dox) were developed and their tumor penetration and anti-cancer activity against 4T1 cells were analyzed. The biodistribution and anti-4T1 breast cancer activities were determined using 4T1 subcutaneous and lung metastasis models. RESULTS: EYLNs-Dox was successfully internalized into macrophages without affecting their viability and was less toxic than Dox. Mac/EYLNs-Dox penetrated the 4T1 tumor spheroids more efficiently and was more effective in inhibiting tumors in vitro. Macrophages significantly enhanced the distribution of EYLNs vectors in both inflammatory and tumor sites, playing a more effective role in the inhibition of tumors. CONCLUSION: EYLNs-Dox can be effectively delivered using macrophages and Mac/EYLNs-Dox might be a promising targeted delivery system for breast cancer.

Leukocyte-Mediated Combined Targeted Chemo and Gene Therapy for Esophageal Cancer.

Poor prognosis of esophageal cancer is associated with limited clinical treatment efficacy and lack of targeted therapies. With advances in nanomedicine, nanoparticle drug delivery systems play increasingly important roles in tumor treatment by enabling the simultaneous delivery of multiple therapeutic agents. We here propose a novel nanovector for targeted combination gene therapy and chemotherapy in esophageal cancer. A novel lipid nanovector (EYLN) was designed to carry the chemotherapy drug doxorubicin (Dox) and small interfering RNA against the lipid anabolic metabolism gene LPCAT1, which we previously showed to be significantly overexpressed in esophageal cancer tissues, and its interference inhibited the proliferation, invasion, and metastasis of esophageal cancer cells. This vector, EYLN-Dox/siLPCAT1, was further coated with leukocyte membranes to obtain mEYLNs-Dox/siLPCAT1. The particle size of the coated nanovector was approximately 136 nm, and the surface zeta potential was -21.18 mV. Compared with EYLNs-Dox/siLPCAT1, mEYLNs-Dox/siLPCAT1 were more easily internalized by esophageal cancer cells due to the LFA-1 highly expressed leukocyte membrane coating and showed significant inhibition of the proliferation, migration, and metastasis of esophageal cancer cells, along with their LPCAT1 expression, through more effective delivery of the drugs. Moreover, the nanovectors showed improved blood circulation time, tissue distribution, tumor targeting, and tumor suppression in a mouse model. Thus, combining chemo and gene therapy with this new nanodelivery system achieved greater therapeutic efficacy, providing a new strategy for the treatment of esophageal cancer.

SLC14A1 (UT-B) gene rearrangement in urothelial carcinoma of the bladder: a case report.

BACKGROUND: Bladder cancer (BC) is a common and deadly disease. Over the past decade, a number of genetic alterations have been reported in BC. Bladder urothelium expresses abundant urea transporter UT-B encoded by Slc14a1 gene at 18q12.3 locus, which plays an important role in preventing high concentrated urea-caused cell injury. Early genome-wide association studies (GWAS) showed that UT-B gene mutations are genetically linked to the urothelial bladder carcinoma (UBC). In this study, we examined whether Slc14a1 gene has been changed in UBC, which has never been reported. CASE PRESENTATION: A 59-year-old male was admitted to a hospital with the complaint of gross hematuria for 6 days. Ultrasonography revealed a size of 2.8 × 1.7 cm mass lesion located on the rear wall and dome of the bladder. In cystoscopic examination, papillary tumoral lesions 3.0-cm in total diameter were seen on the left wall of the bladder and 2 cm to the left ureteric orifice. Transurethral resection of bladder tumor (TURBT) was performed. Histology showed high-grade non-muscle invasive UBC. Immunostaining was negative for Syn, CK7, CK20, Villin, and positive for HER2, BRCA1, GATA3. Using a fluorescence in situ hybridization (FISH), Slc14a1 gene rearrangement was identified by a pair of break-apart DNA probes. CONCLUSIONS: We for the first time report a patient diagnosed with urothelial carcinoma accompanied with split Slc14a1 gene abnormality, a crucial gene in bladder.

lncRNA MORT Regulates Bladder Cancer Behaviors by Downregulating MicroRNA-146a-5p.

BACKGROUND: Long noncoding RNAs (lncRNAs) are involved in the progression of various cancers. lncRNA MORT is downregulated in bladder cancer, while its function in this disease is unknown. METHODS: lncRNA MORT and miR-146a-5p expression in 56 bladder cancer patients was detected by RT-qPCR. Correlations between MORT and miR-146a-5p were analyzed by Pearson's correlation coefficient. CCK-8 and flow transwell assays were applied to examine the behavioral changes in HT-1197 and HT-1376. RESULTS: We found that miR-146a-5p was upregulated, while lncRNA MORT was downregulated in bladder cancer. miR-146a-5p and MORT were inversely and significantly correlated in tumor tissues. Overexpression of miR-146a-5p promoted, while overexpression of lncRNA MORT inhibited the invasion, migration, and proliferation of cells of bladder cancer cell lines. In addition, overexpression of lncRNA MORT inhibited miR-146a-5p; miR-146a-5p overexpression failed to significantly affect lncRNA MORT expression but attenuated its inhibitory effects on cancer cell behaviors. CONCLUSION: lncRNA MORT may regulate bladder cancer cell behaviors by downregulating miR-146a-5p.

Circular RNA hsa_circ_0007142 Is Upregulated and Targets miR-103a-2-5p in Colorectal Cancer.

Circular RNAs (circRNAs) are a large class of endogenous noncoding RNAs that regulate gene expression and mainly function as microRNA sponges. This study aimed to explore the aberrant expression of circRNAs in colorectal cancer (CRC). Using a circRNA microarray, we identified 892 differentially expressed circRNAs between six pairs of CRC and adjacent paracancerous tissues. Among them, hsa_circ_0007142 was significantly upregulated. Further analysis in 50 CRC clinical samples revealed that hsa_circ_0007142 upregulation was associated with poor differentiation and lymphatic metastasis of CRC. Bioinformatic analysis and luciferase reporter assay showed that hsa_circ_0007142 targeted miR-103a-2-5p in CRC cells. Moreover, the silencing of hsa_circ_0007142 by siRNAs decreased the proliferation, migration, and invasion of HT-29 and HCT-116 cells. Taken together, these findings suggest that hsa_circ_0007142 is upregulated in CRC and targets miR-103a-2-5p to promote CRC.

PD-L1 Expression Predicts a Distinct Prognosis in Krukenberg Tumor with Corresponding Origins.

Krukenberg tumor (KT) is an uncommon ovarian metastatic signet-ring cell adenocarcinoma that mostly metastasizes from gastrointestinal carcinoma. Optimal treatment options for KTs are limited. Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have shown remarkable activity in clinical trials for metastatic tumors. Here, we evaluated PD-L1 expression and T cell infiltration in KTs and their corresponding primary tumors. Positive tumor PD-L1 expression was detected in 9 (25.7%) KTs from gastric carcinomas (GCs) and in 20 (66.7%) KTs from colorectal carcinomas (CRCs). Patient survival was assessed according to the PD-L1 status and CD8+ T cell density. Positive tumor PD-L1 expression in KTs from GCs was associated with poor prognosis. In contrast, positive tumor PD-L1 expression in KTs from CRCs was associated with an improved prognosis. We analyzed copy number variations of the PD-L1 gene in KTs. PD-L1 expression was higher in cases with copy number gains. The T cell densities within KTs and their corresponding primary tumors were compared. The densities of CD8+ T cells correlated significantly between the primary tumors and KTs from the same case. Taken together, the research further highlighted targets for immune-based therapy in KTs from GCs and CRCs.

FGFRL1 Promotes Ovarian Cancer Progression by Crosstalk with Hedgehog Signaling.

Fibroblast growth factor receptor-like-1 (FGFRL1) has been identified as the fifth fibroblast growth factor receptor. So far, little is known about its biological functions, particularly in cancer development. Here, for the first time, we demonstrated the roles of FGFRL1 in ovarian carcinoma (OC). An array and existing databases were used to investigate the expression profile of FGFRL1 and the relationship between FGFRL1 expression and clinicopathological parameters. FGFRL1 was significantly upregulated in OC patients, and high FGFRL1 expression was correlated with poor prognosis. In vitro cell proliferation, apoptosis and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the role of FGFRL1. Loss of function of FGFRL1 significantly influenced cell proliferation, apoptosis, and migration of OC cells in vitro and tumor growth in vivo. Chromatin immunoprecipitation PCR analysis and microarray hybridization were performed to uncover the mechanism. FGFRL1 expression could be induced by hypoxia through hypoxia-inducible factor 1α, which directly binds to the promoter elements of FGFRL1. FGFRL1 promoted tumor progression by crosstalk with Hedgehog (Hh) signaling. Taken together, FGFRL1 is a potential predictor and plays an important role in tumor growth and Hh signaling which could serve as potential therapeutic targets for the treatment of OC.

[Comparison of the efficacy and safety of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin chemotherapy regimens in the treatment of advanced gastric cancer].

OBJECTIVE: To observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients. METHODS: A total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed. RESULTS: The objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients. CONCLUSIONS: Both CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.

Elevated expression of RIT1 correlates with poor prognosis in endometrial cancer.

RIT1, (Ras-like without CAAX1), the founding member of a novel branch of the Ras subfamily, mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation, and it may play crucial oncogenic role in human cancer. The purpose of the current study was to characterize the expression pattern of RIT1 and assess the clinical significance of RIT1 expression in endometrial cancer patients. The mRNA and protein expression of RIT1 was significantly overexpressed in 7 endometrial cancer cell lines by qPCR and Western blot, respectively. In addition, RIT1 mRNA expression was elevated in 36 freshly frozen endometrial cancer tissues compared to 21 non-cancerous endometrial tissue samples. Similar results were observed by analyzing GEO datasets. Immunohistochemistry was used to examine the protein expression of RIT1 in two tissue microarrays containing 257 cases of tumor and 31 non-tumor tissues, which showed that elevated expression of RIT1 was significantly correlated with pathological type, clinical stage, grade and vascular invasion. Importantly, Kaplan-Meier survival analysis indicated that RIT1 expression was associated with overall survival of endometrial cancer patients. Multivariate Cox regression analysis revealed that RIT1 expression was one of the independent prognostic factors for endometrial cancer patients. Furthermore, RIT1 combined with other clinicopathological risk factors was a more significant model in ROC curve comparison. In conclusion, elevated expression of RIT1 may contribute to the progression of endometrial cancer and thus may serve as a novel prognostic marker and a promising molecular target for the treatment of endometrial cancer.

[Risk factors of benign anastomostic strictures after esophagectomy with cervical reconstruction].

OBJECTIVE: To identify the risk factors of benign cervical anastomotic strictures after esophagectomy. METHODS: Clinical data of 946 esophageal cancer patients undergoing esophagectomy with cervical anastomosis between 2003 and 2012 were analyzed retrospectively. Benign stricture was defined as dysphagia for which endoscopic dilation of the anastomosis was needed. Histologically proven malignant stricture was not regarded as benign stricture. χ(2) test and logistic regression model were used for univariate and multivariate analysis respectively. RESULTS: A total of 146 patients(16.5%) developed benign stricture during follow-up. Univariate analysis showed that the patients with cardiovascular disease (P=0.001), diabetes mellitus(P=0.041), gastric tube reconstruction(P=0.050), end-to-end anastomosis (P=0.013), or postoperative anastomotic leakage(P=0.008) had higher stricture rate. Multivariate analysis revealed that cardiovascular disease(P=0.004), gastric tube reconstruction (P=0.026), end-to-end anastomosis(P=0.043), and postoperative anastomotic leakage(P=0.001) were independently predictive factors for development of benign stricture. CONCLUSIONS: The benign cervical stricture rate after esophagetomy with cervical gastric anastomosis is quite high. In order to prevent benign stricture formation, end-to-end anastomosis should be avoid. Blood pressure should be controlled for those with cardiovascular disease. Endoscopic dilation in an earlier stage postoperatively should be considered for those who develop anastomotic leakage.

JSI124 inhibits breast cancer cell growth by suppressing the function of B cells via the downregulation of signal transducer and activator of transcription 3.

JSI-124, also known as cucurbitacin I, is a selective inhibitor of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and in vitro and in vivo studies have found that it has anti-tumor and anti-proliferative properties. However, the role of JSI124 in tumor-associated B cells has yet to be elucidated. The present study demonstrated that STAT3 is significantly activated in the B cells of patients with breast cancer. Furthermore, a 4T1 tumor-bearing mouse model revealed that JSI124 effectively inhibited tumor growth. Moreover, the STAT3 levels in the B cells of the JSI124-treated mice were found to be significantly decreased. B cells from normal Balb/c mice, the 4T1-bearing mice and the JSI124-treated 4T1 mice were purified and intravenously injected into the 4T1-bearing Balb/c mice. Tumor growth data showed that the 4T1 tumor mouse-derived B cells, which exhibited a higher level of STAT3, promoted tumor growth, while the JSI124-treated 4T1 mouse-derived B cells had a tumor suppressor function. Furthermore, the B cells from the normal Balb/c mice were treated with phosphate-buffered saline, JSI124 and 4T1 tumor cells, then the B cell STAT3 levels were analyzed. Following injection into the 4T1 mice, the 4T1 cell-treated B cells were observed to enhance tumor growth, while the JSI124-treated B cells were found to inhibit the growth of 4T1 tumors in vivo. These findings show a novel role of JSI124 in tumor suppression through the downregulation of the expression of STAT3 in tumor-associated B cells.

microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells.

Despite advances in the understanding of breast cancer, patients most commonly have a poor prognosis, particularly those with triple negative breast cancer (TNBC). microRNAs (miRNAs) are endogenous non­coding small RNAs, and their aberrant expression is linked to numerous malignancies. In the present study, the expression levels of miR­200c in patients with TNBC were analyzed and it was identified that miR­200c was downregulated in TNBC samples, compared with that in normal adjacent tissues. miR­200c was overexpressed in the TNBC cell line MDA­MB­231 and its functions were studied in vitro and in vivo. An in vitro study revealed that the overexpression of miR­200c inhibited MDA­MB­231 cell proliferation and resulted in the induction of apoptosis. The in vivo data indicated that the overexpression of miR­200c significantly inhibited tumor growth and increased the rate of apoptosis. Target prediction revealed that the X­linked inhibitor of apoptosis (XIAP) had putative complementary sequences to miR­200c, which was confirmed by a dual luciferase reporter assay. Western blot analysis further demonstrated that the expression of XIAP was markedly reduced and that caspase­3 was highly activated by the overexpression of miR­200c. These findings suggested that miR­200c may function as a tumor suppressor gene in TNBC, at least partly via directly targeting XIAP, and may therefore act as a potential therapeutic target in the development of novel treatment strategies for TNBC.

[The correlation between chemotherapeutic efficacy and breast cancer susceptibility gene 1 and class IIIß-tubulin protein expression in non-small cell lung cancer patients].

OBJECTIVE: To investigate the predictive value of breast cancer susceptibility gene 1 (BRCA1) and class IIIß-tubulin protein expression in tumor tissue for the efficacy of taxol and cisplatin combined chemotherapy (TP) in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. METHODS: A total of 92 stage IIIB/IV NSCLC patients were recruited with 87 patients evaluated. Bronchoscopy or lung puncture tumor biopsy samples were obtained with BRCA1 and class IIIß-tubulin protein expression examined immunohistochemically before chemotherapy. The patients were randomly assigned to be received 4 to 6 cycles of TP chemotherapy regiments and followed up until death or lost. Response rate (RR), overall survival (OS) and time to tumor progression (TTP) were assessed. RESULTS: Among the 87 evaluated patients, the positive expression rates of BRCA1 and class IIIß-tubulin were 57.5% (50/87) and 48.3% (42/87) respectively. There was no significant difference in clinical characteristics among patients with different positive expression rate. According to different expression of BRCA1 and class IIIß-tubulin, the patients were divided into four groups: group A (low expression of both BRCA1 and class IIIß-tubulin), group B (high expression of both BRCA1 and class IIIß-tubulin), group C (high expression of only BRCA1) and group D (high expression of only class IIIß-tubulin). The RR was higher in group A than other three groups (60.7%, 34.8%, 9/19 and 6/17 respectively). The OS and TTP were longer in group A than other three groups [OS: (539.4 ± 17.6) days, (267.2 ± 20.5) days, (325.6 ± 24.1) days and (283.7 ± 26.2) days respectively; TTP: (256.9 ± 28.4) days, (143.8 ± 17.6) days, (179.3 ± 19.8) days and (152.6 ± 23.5) days respectively]. There were no significant differences among the other three groups. CONCLUSIONS: The expression level of BRCA1 and class IIIß-tubulin in tumor tissue is probably a predictor for the efficacy of TP chemotherapy in NSCLC patients. TP chemotherapy is more suitable for the NSCLC patients with lower expression of both BRCA1 and class IIIß-tubulin. Our study may provide a new sight for tailored chemotherapy in NSCLC patients.