Plasma membrane gp96 enhances invasion and metastatic potential of liver cancer via regulation of uPAR

Targeted therapy is currently under intensive investigation due to the resistance of liver cancer to cytotoxic chemotherapies. Dissecting the molecular events that drive the progression of liver cancer and defining specific targets are urgently needed to develop efficient tailored therapies. Cell membrane gp96 (mgp96) has been implicated in tumor growth and malignancy. Here, we explored the functional and clinical relevance of mgp96 in liver cancer. We found that elevated mgp96 abundance was associated with tumor metastasis and recurrence in patients with primary liver tumors. Decreased KDELR1 levels in hepatoma cells contribute to cell membrane translocation of the normally ER‐resident gp96. Urokinase‐type plasminogen activator receptor (uPAR) was identified as a mgp96 client protein, and mgp96 stabilized uPAR protein. Our clinical results proved that elevated mgp96 abundance is positively correlated with uPAR expression levels in liver tumors. We further provided evidence that targeting mgp96 with siRNA or a specific mAb that blocked the mgp96‐uPAR interaction led to inhibited cell growth, survival, and invasion in vitro, as well as the suppression of liver tumor growth and metastasis in vivo. mgp96 promotes liver cancer progression through increasing the protein stability and signaling of uPAR, and may be a new promising target for suppressing uPAR‐mediated tumor growth and metastasis in liver cancer.     

Mutation analysis in patients with total sperm immotility

Purpose

Perform the genetic characterization of five patients with total sperm immotility using Sanger sequencing and Whole Exome Sequencing (WES), in order to increase the knowledge on the genetics of sperm immotility and, ultimately, allow the identification of potential genetic markers for infertility.

Methods

Prospective study at a University Medical school. We analysed five men with total sperm immotility, four with dysplasia of the fibrous sheath (DFS), associated with disruption of several axonemal structures, and one patient with situs inversus totalis, which showed absence of dynein arms (DA) and nexin bridges. We screened 7 genes by Sanger sequencing, involved in sperm motility and associated to ultrastructural defects found in these patients (CCDC39, CCDC40, DNAH5, DNAI1, RSPH1, AKAP3 and AKAP4). Additionally, we performed WES analysis in the patient with situs inversus.

Results

We identified nine new DNA sequence variants by WES. Two of these variants were considered particularly relevant: a homozygous missense change in CCDC103 gene (c.104G > C, p.R35P) probably related with absence of dynein arms; the other in the INSL6 gene (c.262_263delCC) is thought to be also involved in sperm immotility.

Conclusions

Our work suggests that WES is an effective strategy, especially as compared with conventional sequencing, to study highly heterogenic genetic diseases, such as sperm immotility. For future work we expect to expand the analysis of WES to the other four patients and complement findings with expression analysis or functional studies to determine the impact of the novel variants.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-015-0474-6) contains supplementary material, which is available to authorized users.     

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in non-small cell lung cancer patients: a meta-analysis

The insulin-like growth factor receptor-1 (IGF1R) plays an important role in cancer progression. Previous studies have been controversial with respect to the associations between IGF1R expression and non small cell lung cancer (NSCLC) prognosis. Thus, we performed a meta-analysis to investigate the prognostic value of IGF1R expression in NSCLC patients and the relationship between the expression of IGF1R and clinical characteristics. Two independent reviewers searched PubMed, Embase, Ovid Medline and CNKI to identify eligible studies. Overall survival (OS), disease free survival (DFS) and clinicopathological characteristics were collected from included studies. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. 17 studies comprising 3,294 patients were included in this meta-analysis. The results showed IGF1R positive expression was associated with an unfavorable DFS in NSCLC patients on univariate analysis (HR = 1.26, 95% CI: 1.09-1.46, P = 0.002) and multivariate analysis (HR = 1.49, 95% CI: 1.01-2.20, p = 0.045), but the relationship between IGF1R expression and OS have no significant difference on univariate analysis (HR = 0.91, 95% CI: 0.82-1.01, P = 0.157) and multivariate analysis (HR = 0.79, 95% CI: 0.45-1.41, P = 0.427). Ever smoking and smaller tumor size (T1 or T2) were associated with IGF1R positive expression: pooled OR 1.45 (1.13-1.85) and pooled OR 0.61 (0.60-0.95). Our results suggested IGF1R positive expression as an unfavorable factor for DFS in NSCLC patients, and IGF1R expression was associated with smoking status and tumor size.     

Propensity-matched comparison of video-assisted thoracoscopic with thoracotomy lobectomy for locally advanced non–small cell lung cancer

Objective

We evaluated whether video-assisted thoracoscopic lobectomy for locally advanced non–small cell lung cancer could be performed safely and with acceptable long-term outcomes by our improved technique and compared with standard thoracotomy lobectomy in a well-balanced population.

The importance of actual tumor growth rate on disease free survival and overall survival in laryngeal squamous cell carcinoma

Background and purpose

Evaluation of the variation in tumor growth rate and the influence of tumor growth rate on disease free survival (DFS) and overall survival (OS) in laryngeal squamous cell carcinoma (LSCC).

Material and methods

We delineated tumor volume on a diagnostic and planning CT scan in 131 patients with laryngeal squamous cell carcinoma and calculated the tumor growth rate. Primary endpoint was DFS. Follow up data were collected retrospectively.

Results

A large variation in tumor growth rate was seen. When dichotomized with a cut-off point of −0.3 ln(cc/day), we found a significant association between high growth rate and worse DFS (p = 0.008) and OS (p = 0.013). After stepwise adjustment for potential confounders (age, differentiation and tumor volume) this significant association persisted. However, after adjustment of N-stage association disappeared. Exploratory analyses suggested a strong association between N-stage and tumor growth rate.

Conclusions

In laryngeal squamous cell carcinoma, there is a large variation in tumor growth rate. This tumor growth rate seems to be an important factor in disease free survival and OS. This tumor growth rate is independent of age, differentiation and tumor volume associated with DFS, but N-stage seems to be a more important risk factor.     

EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive,HER2-negative breast cancer

The EndoPredict (EP) signature is a prognostic 11-gene expression signature specifically developed in ER+/HER2– node-negative/positive breast cancer. It is associated with relapse-free survival in patients treated with adjuvant hormone therapy, suggesting that EP low-risk patients could be treated with adjuvant hormone therapy alone whereas high-risk patients would deserve addition of adjuvant chemotherapy. Thus, it is important to determine whether EP high-risk patients are or are not more sensitive to chemotherapy than low-risk patients. Here, we have assessed the EP predictive value for pathological complete response to neoadjuvant chemotherapy in ER+/HER2– breast cancer. We gathered gene expression and histoclinical data of 553 pre-treatment ER+/HER2– breast carcinomas treated with anthracycline-based neoadjuvant chemotherapy. We searched for correlation between the pathological complete response (pCR) and the EP score-based classification. The overall pCR rate was 12%. Fifty-one percent of samples were classified as low-risk according to the EP score and 49% as high-risk. EP classification was associated with a pCR rate of 7% in the low-risk group and 17% in the high-risk group (p < 0.001). In multivariate analysis, the EP score remained significantly associated with pCR. Many genes upregulated in the high-risk tumours were involved in cell proliferation, whereas many genes upregulated in the low-risk tumours were involved in ER-signalling and stroma. Despite higher chemosensitivity, the high-risk group was associated with worse disease-free survival. In conclusion, EP high-risk ER+/HER2– breast cancers are more likely to respond to anthracycline-based chemotherapy.     

大剂量干扰素治疗是黑素瘤术后辅助治疗的首选方案（附450例观察）

目的:回顾分析黑素瘤患者术后辅助治疗的临床资料,评价不同的术后辅助治疗方案对患者无病生存(disease-free survival,DFS)的影响。方法:收集2006年1月至2009年7月我科就诊的450例Ⅰ至Ⅲ期恶性黑素瘤患者(来自全国28个省市,男239、女211例,年龄12～85岁,中位年龄51岁)的临床资料。所有患者均接受手术治疗,术后辅助治疗包括大剂量干扰素治疗(2 200万IU静注,每周5次,共4周;900万IU皮下注射,每周3次,共11个月)、化疗(方案以达卡巴嗪或替莫唑胺为主,也有联合顺铂、紫杉醇、长春新碱等药物的方案)、化疗联合放疗和单纯放疗(原发灶或淋巴结引流区域放疗,剂量40～60 Gy)等4个方案。结果:450例Ⅰ至Ⅲ期恶性黑素瘤患者,分别行原发病灶的局部切除、扩大切除或扩大切除联合区域淋巴结切除。术后184例患者未接受任何治疗、84例患者接受了化疗、25例患者接受了联合放化疗、2例患者接受了单纯放疗,该4组患者的中位DFS分别为13个月、20个月、29个月、23个月;而155例接受了大剂量干扰素治疗患者的中位DFS尚未达到。化疗的不良反应主要为消化道不良反应、骨髓抑制、肝功能损伤等;干扰素治疗的不良反应主要有白细胞降低、发热、乏力、转氨酶升高、厌食,其中白细胞降低以及转氨酶升高达3或4级不良反应的发生率分别为15%和10%;经对症处理后,患者的不良反应均恢复正常。结论:Ⅰ至Ⅲ期恶性黑素瘤患者的手术切除方式以及术后辅助治疗的方案对于患者的DFS极为重要,术后接受大剂量干扰素治疗延长恶性黑素瘤患者DFS的效果最好,且安全性较好。     

TS expression predicts postoperative recurrence in adenocarcinoma of the lung

Background

Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers for either selecting appropriate candidates or for predicting clinical recurrence exist.

Methods

Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expressions in the primary lung adenocarcinoma by immunohistochemisty.

Results

The strong expression of TS and DHFR was identified in 39 (21.3%) and 120 (65.6%) patients, respectively. The strong TS expression was identified in 11 (39.3%) of 28 patients and 28 (18.1%) of 155 patients in patients with and without recurrence, respectively (p = 0.012). The strong DHFR expression was also identified in 23 (82.1%) and 97 (62.6%) of the patients with and without recurrence, respectively (p = 0.045). Logistic regression models indicated the strong TS expression to be an independent factor for tumor recurrence. The strong TS and DHFR expression was associated with a poorer disease-free survival (DFS) according to the survival analysis. A multivariate analysis demonstrated the strong TS expression to be independently associated with an increased risk for poor DFS.

Conclusions

The strong TS expression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery.