PABPN1 functions as a predictive biomarker in colorectal carcinoma.

PURPOSE: PABPN1 acts as a modulator of poly(A) tail length and alternative polyadenylation. This research was aimed to explore the role of PABPN1 in colorectal cancer (CRC). METHODS: Public databases were performed to analyze expression, location, roles of prognosis and tumor immunity and interaction with RNAs and proteins of PABPN1. To investigate PABPN1 expression in tissues, 78 CRC specimens were collected to conduct IHC, and 30 pairs of frozen CRC and corresponding adjacent normal tissues were used to conduct qRT-PCR and WB. In addition, in vitro experiments were then carried out to identify the role of PABPN1 in CRC. RESULTS: Compared with normal tissues, PABPN1 expression was significant higher in CRC. Its high level predicted poor outcome of CRC. Th1 and Treg had significant negative relationships not only with PABPN1 expression, but also with six molecules interacting with PABPN1, including IFT172, KIAA0895L, RECQL4, WDR6, PABPC1 and NCBP1. In addition, PABPN1 had negative relationships with quite a few immune markers, such as CSF1R, IL-10, CCL2 and so on. In cellular experiments, silencing PABPN1 inhibited proliferation and promoted apoptosis in HCT-116 CRC cells. CONCLUSION: In summary, PABPN1 might become a novel biomarker and correlate with tumor immunity in CRC.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Pan-cancer analysis of LncRNA XIST and its potential mechanisms in human cancers.

Background: X-inactive specific transcript (XIST), it has been found, is abnormal expression in various neoplasms. This work aims to explore its potential molecular mechanisms and prognostic roles in types of malignancies. Methods: This research comprehensively investigated XIST transcription across cancers from Oncomine, TIMER 2.0 and GEPIA2. Correlations of XIST expression with prognosis, miRNAs, interacting protens, immune infiltrates, checkpoint markers, mutations of tumor-associated genes and promoter methylation were also analyzed by public databases. In addition, 98 BRCA samples were collected to investigate XIST expression and evaluate its clinicopathological value. Results: In public databases, compared to normal tissues, XIST was lower in BRCA, CESC, COAD and so on, but increased in KIRC and PRAD. Databases also showed that XIST was a good indicator of prognosis in BRCA, COAD and so on, but a bad one in KIRC, KIRP and so on. From starBase, we found 29 proteins interacting with XIST, and identified 4 miRNAs which might be sponged by XIST in cancers. Furthermore, XIST was linked with immune infiltration, especially T cell CD4+, and was related to over 20 immune checkpoint markers. Moreover, several tumor-associated gene mutations and promoter methylation were negatively related to its expression. In addition, IHC showed that XIST in BRCA was obviously lower in comparison of normal tissues and was negatively related to lymph node invasion and TNM stage. Conclusion: In summary, abnormal expression of XIST influenced prognosis, miRNAs and immune infiltration across cancers, especially BRCA.

Anterior cruciate ligament rupture in a patient with Albers-Schonberg disease.

BACKGROUND: Osteopetrosis is an uncommon inherited disease marked with elevated bone density and frequent bone fractures owing to flawed osteoclast activity. Autosomal dominant osteopetrosis type 2 (ADO-2), a benign form of osteopetrosis, is also known as Albers-Schonberg disease. CASE PRESENTATION: We report the first successful anterior cruciate ligament (ACL) reconstruction surgery for ACL rupture treatment in a 30-year-old female with ADO-2, who carried a heterozygous missense mutation c.2227C > T (p.Arg743Trp) in exon 23 of the chloride channel 7 (CLCN7) gene. Histopathological analysis of the ruptured ACL sample revealed massive calcium salt deposition in the ligament tissue. A ligament advanced reinforcement system (LARS) artificial ligament was employed in her ACL reconstruction surgery. At her final 16 month's follow-up, she reported no knee instability symptoms and other complications. The range of motion of the affected knee was good. The side-to-side difference in knee laxity, as evidenced by a KT-1000 arthrometer was 0.9 mm. The Lysholm score improved from 45 before operation to 83 after operation. The Tegner activity score improved from 1 before operation to 4 after operation. CONCLUSIONS: Our findings further confirmed that the newly identified mutated locus (p.Arg743Trp) may lead to acid secretion disorders at different sites (including calcified ACL in our case). In terms of clinical treatment, ligament reconstruction surgery in patients with Albers-Schonberg disease presents a unique challenge to orthopedic surgeons and requires further preparation and time.

Gross perianal embryonal rhabdomyosarcoma with severe multiple bone metastases throughout the body: a case report.

In adults, embryonal rhabdomyosarcoma (ERMS) is rare and has a poor prognosis. Giant perianal ERMS with severe multiple bone metastases at initial diagnosis has not been reported and lacks effective treatment options. This current case report describes a 31-year-old female patient that presented with a large lump on the right side of the anus. ERMS was diagnosed, accompanied by multiple bone metastases throughout the body and severe thrombocytopenia. She had an extremely low platelet count at initial diagnosis, making systemic chemotherapy inappropriate. Genetic testing did not help identify effective targeted drugs. A multi-target tyrosine kinase inhibitor, anlotinib, was selected to control the tumours combined with local radiotherapy to relieve pain. The lump became smaller and this reduction was maintained for 5 months. At 7 months after the diagnosis, the patient died of thrombocytopenia. This current case may provide supportive evidence for a potential treatment for patients with advanced ERMS, especially those not suitable for chemotherapy or surgery.

Roles of eIF3m in the tumorigenesis of triple negative breast cancer.

BACKGROUND: Without targets, triple negative breast cancer (TNBC) has the worst prognosis in all subtypes of breast cancer (BC). Recently, eukaryotic translation initiation factor 3 m (eIF3m) has been declared to be involved in the malignant progression of various neoplasms. The aim of this study is to explore biological functions of eIF3m in TNBC. METHODS: Multiple databases, including Oncomine, KM-plotter and so on, were performed to analyze prognosis and function of eIF3m in TNBC. After transfection of eIF3m-shRNA lentivirus, CCK-8, colony formation assay, cell cycle analysis, wound healing assay, transwell assays, mitochondrial membrane potential assay and cell apoptosis analysis were performed to explore the roles of eIF3m in TNBC cell bio-behaviors. In addition, western blotting was conducted to analyze the potential molecular mechanisms of eIF3m. RESULTS: In multiple databases, up-regulated eIF3m had lower overall survival, relapse-free survival and post progression survival in BC. EIF3m expression in TNBC was obviously higher than in non-TNBC or normal breast tissues. Its expression in TNBC was positively related to differentiation, lymph node invasion and distant metastasis. After knockdown of eIF3m, cell proliferation, migration, invasion and levels of mitochondrial membrane potential of MDA-MB-231 and MDA-MB-436 were all significantly suppressed, while apoptosis rates of them were obviously increased. In addition, eIF3m could regulate cell-cycle, epithelial-mesenchymal transition and apoptosis-related proteins. Combined with public databases and RT-qPCR, 14 genes were identified to be modulated by eIF3m in the development of TNBC. CONCLUSIONS: eIF3m is an unfavorable indicator of TNBC, and plays a vital role in the process of TNBC tumorigenesis.

Roles and correlation of FOXA1 and ZIC1 in breast cancer.

The aim of this study was to evaluate the prognostic role of Forkhead box A1 (FOXA1) in breast cancer and determine the relationship between FOXA1 and zinc finger of the cerebellum 1 (ZIC1). BCIP, GEPIA, and Oncomine databases were used to detect expression of FOXA1 and assess prognostic roles of FOXA1 and ZIC1 in invasive breast tumors. A total of 113 female invasive breast cancer cases were collected to investigate FOXA1 and ZIC1 expression via immunohistochemistry. Twenty pairs of frozen-thawed tumors were used to select reliable indicators via western blotting and real-time quantitative polymerase chain reaction. In addition, Kaplan-Meier curves and Cox regression analysis were performed to analyze the overall survival (OS) and relapse-free survival. Multiple databases showed that FOXA1 expression was elevated in invasive breast cancer and negatively related to ZIC1. BCIP database also displayed a poor prognosis of high FOXA1 and low ZIC1. FOXA1 was positively associated with tumor size, grading, lymph node metastasis, and Tumor Node Metastasis (TNM) staging, while ZIC1 expression was negatively related to grading, lymph node metastasis, and TNM staging. In Kaplan-Meier and Cox regression analysis, FOXA1 negative group and ZIC1 positive group had better OS rate and recurrence-free survival rate. In addition, a joint evaluation showed that "FOXA1- ZIC1+" had the highest OS and relapse-free survival, but "FOXA1+ ZIC1-" had the lowest ones. FOXA1 was negatively related to ZIC1 in breast cancer and they had different roles in clinicopathology and prognosis. Combined examination of FOXA1 and ZIC1 could bring more benefit to breast cancer patients.

High expression of eukaryotic initiation factor 3M predicts poor prognosis in colon adenocarcinoma patients.

Eukaryotic initiation factor 3 subunit M (EIF3M) is required for key steps in the initiation of protein synthesis, and dysregulation of EIF3M is associated with tumorigenesis. This study aimed to explore the clinicopathological and prognostic role of EIF3M in patients with colon adenocarcinoma. A total of 82 pathology specimens, 20 freeze-thawed tumors and 80 healthy controls were used to investigate the expression of EIF3M in colon adenocarcinoma through immunohistochemistry, western blotting, RT-qPCR and ELISA. In addition, Kaplan-Meier curves and Cox regression analysis were used to analyze overall survival (OS) and disease-free survival (DFS). Furthermore, the Oncomine database was used for analyzing EIF3M expression. The positive rate of EIF3M in colon adenocarcinoma was higher compared with that in normal colon tissues (62.20% vs. 29.27%; P<0.001). The mean score of EIF3M was also higher in colon adenocarcinoma compared with normal colon tissue (17.28±10.05 vs. 6.53±4.87; P<0.001). The levels of EIF3M expression in freeze-thawed tumors and serum from 20 patients with colon adenocarcinoma were higher than those in normal tissues and serum from healthy controls, respectively (P<0.001). In addition, positive expression of EIF3M was associated with tumor size (P=0.002) and Dukes' stage (P<0.001). In multivariate Cox regression analysis, EIF3M expression was an independent prognostic factor for OS (P=0.003) and DFS (P=0.001). Oncomine database analysis showed a higher expression of EIF3M expression in colon adenocarcinoma compared with normal colon tissues, colon squamous cell carcinomas or gastrointestinal stromal tumors. In conclusion, EIF3M expression was associated with tumor size and Dukes' stage in colon adenocarcinoma. Hence, EIF3M is a potential prognostic indicator for colon adenocarcinoma.

Prognostic and clinicopathological value of ZIC1 in patients with cervical squamous cell carcinoma.

The aim of the present study was to analyze the differences in zinc finger of the cerebellum 1 (ZIC1) expression between cervical cancer tissue, precancer tissue and normal cervical tissue to determine its clinicopathological and prognostic value in cervical squamous cell carcinoma (CSCC). Reverse transcription-quantitative PCR was used to determine the mRNA expression levels of ZIC1 in 569 fresh-frozen biopsy tissues, and immunohistochemistry was performed to detect ZIC1 protein expression in 80 CSCC tissues and 320 cervical intraepithelial neoplasia (CIN) grade III samples. The association of ZIC1 expression with the clinicopathological characteristics of CSCC was then analyzed using Cox regression analysis, and Kaplan-Meier curves were used to analyze the prognostic value. The level of ZIC1 mRNA expression in CSCC was significantly lower compared with normal cervical tissues and CIN I-III tissues (P<0.001). There was a negative correlation between ZIC1 immunoreactivity score (IRS) in CSCC tissue and adjacent noncancerous tissue (R=-0.279; P=0.012); the mean IRS of ZIC1 in CSCC tissue was 5.36±3.48, which was significantly lower compared with the corresponding adjacent noncancerous tissues (11.31±5.68; P<0.001) and CIN III samples (10.42±1.54; P<0.001). In addition, expression of ZIC1 was negatively associated with International Federation of Gynecology and Obstetrics (FIGO) stage (P=0.027) and lymph node metastasis (P<0.001). In Cox regression analysis, ZIC1 expression [hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.40-0.92; P=0.018), FIGO staging (HR, 3.55; 95% CI, 2.35-5.37; P<0.001) and lymph node metastasis (HR, 2.50; 95% CI, 1.62-3.86; P<0.001) were three independent prognostic factors of overall survival. Furthermore, ZIC1 expression was also associated with disease-free survival (P=0.003). These results suggest that ZIC1 expression in CSCC may be lower than in normal cervical tissues or CIN tissues, and high expression of ZIC1 may be negatively associated with FIGO stage and lymph node metastasis. Therefore, ZIC1 may be a promising biomarker for the prognosis of CSCC.

ZIC1 acts a tumor suppressor in breast cancer by targeting survivin.

In this study, we aimed to identify the tumor suppressive roles of zinc finger of the cerebellum 1 (ZIC1) in patients with malignant breast neoplasms and to examine the association between ZIC1 and survivin expression. For this purpose, 140 invasive breast cancer specimens, 1,075 RNA breast cancer samples from The Cancer Genome Atlas (TCGA), 6 human breast cancer cell lines and MCF-10A normal breast epithelial cells were selected in order to compare the expression level of ZIC1 with that of survivin via immunohistochemistry and western blot analysis. Subsequently, the MDA-MB-231 and SK-BR3 cells with a lower ZIC1 expression were transfected with rLV-Zic1-PGK-Puro lentivirus or rLV-ZsGreen-PGK­Puro lentivirus in order to observe any alterations in cell proliferation and apoptosis through MTT assay, colony formation assay, mitochondrial membrane potential assay and flow cytometric analysis, and to analyze the modulation of molecular mechanisms by western blot analysis. In addition, xenograft mouse models were constructed to explore the role of ZIC1 in the growth of implanted tumors. The results revealed that ZIC1 negatively correlated with survivin in tumors and cells, and a higher ZIC1 RNA expression indicated a better overall survival in the 1,075 TCGA RNA breast cancer samples. In vitro, the overexpression of ZIC1 inhibited cell proliferation, reduced mitochondrial membrane potential and promoted the apoptosis of the MDA-MB-231 and SK-BR3 breast cancer cells by inactivating the Akt/mTOR/P70S6K pathway, suppressing survivin expression, modulating the cell cycle, releasing cytochrome c (Cyto-c) into the cytosol and activating caspase proteins. In vivo, an elevated ZIC1 expression suppressed the growth of implanted tumors and downregulated survivin expression in tumors. On the whole, the findings of this study demonstrate that ZIC1 plays a tumor suppressive role in breast cancer, by targeting surviving, significantly downregulating its expression.

Clinicopathologic and Prognostic Significance of the Zinc Finger of the Cerebellum Family in Invasive Breast Cancer.

PURPOSE: Five members of the zinc finger of the cerebellum (ZIC) family-ZIC1, ZIC2, ZIC3, ZIC4, and ZIC5-have been shown to be involved in various carcinomas. Here, we aimed to explore the clinicopathologic and prognostic roles of ZIC family members in invasive breast cancer patients using immunohistochemical analysis, western blotting analysis, and real-time quantitative polymerase chain reaction (RT-qPCR). METHODS: A total of 241 female invasive breast cancer patients who underwent radical mastectomy between 2009 and 2011 were enrolled. ZIC proteins in 241 pairs of breast tumors and corresponding normal tissues were investigated using immunohistochemistry and the clinicopathologic roles of proteins were analyzed using Pearson's chi-square test. Kaplan-Meier curves and Cox regression analysis were also used to analyze the prognostic value of the ZIC proteins. In addition, 12 pairs of fresh-frozen breast tumors and matched normal tissues were used in the western blotting analysis and RT-qPCR. RESULTS: Only ZIC1 expression in normal tissues was obviously higher than that in tumors (p<0.001). On multivariate analysis, ZIC1 expression (in overall survival analysis: hazard ratio [HR], 0.405, 95% confidence interval [CI], 0.233-0.702, p=0.001; in disease-free survival analysis: HR, 0.395, 95% CI, 0.234-0.669, p=0.001) was identified as a prognostic indicator of invasive breast cancer. CONCLUSION: ZIC1, but not the other proteins, was obviously decreased in breast tumors and associated with clinicopathologic factors. Thus, ZIC1 might be a novel indicator to predict the overall and disease-free survival of invasive breast cancer patients.

Prognostic value of SPARCL1 in patients with colorectal cancer.

Secreted protein acidic and rich in cysteine-like 1 (SPARCL1), a member of extracelluar matrix glycoprotein, has been reported to be associated with various tumor types. The present study aimed to evaluate the prognostic value of SPARCL1 in patients with colorectal cancer. Tissue microarray blocks were constructed based on 79 patients who underwent radical surgery at the Kunshan First People's Hospital between 2008 and 2010. Thirty pairs of fresh-frozen tissues were also obtained for total protein extraction. The expression of SPARCL1 protein was analyzed using immunohistochemistry and western blotting analyses, and the association between overexpressed SPARCL1 and clinicopathological factors was evaluated. Survival analysis with Kaplan Meier curves and Cox regression analysis was used to analyze the prognostic value of SPARCL1. According to western blot analyses, SPARCL1 protein expression in colorectal tumors was significantly lower compared with corresponding normal tissues. The expression of SPARCL1 was markedly decreased from differentiation I to III, and the negative rate of SPARCL1 was higher at Duke's stage C compared with B. Though without any difference between 'positive' and 'negative' in overall survival, significantly higher survival in patients with positive SPARCL1 expression at Duke's stage B was detected in the present study. These results indicated that SPARCL1 may be a potential tumor suppressor gene and associated with good prognosis.

p-Akt as a potential poor prognostic factor for gastric cancer: a systematic review and meta-analysis.

To understand the relationship between p-Akt expression and the prognosis of patients with gastric cancer, we searched six databases, Pubmed, EMBASE, Cochrane Library, CNKI, Wanfang and CBM for relevant articles in order to conduct this metaanalysis. The pooled hazard ratios and corresponding 95%CI of overall survival were calculated to evaluate the prognostic value of p-Akt expression in patients with gastric cancer. With 2261 patients combined from 13 available studies, the pooled HR showed a poor prognosis in patients with gastric cancer in the univariate analysis (HR=1.88, 95%CI:1.45-2.43, P<0.00001), and the group "univariate analysis+estimate" (HR=1.41, 95%CI: 1.01-1.97, P=0.04), but not in multivariate analysis (HR=0.66, 95%CI: 0.29-1.52, P=0.33) and estimate (HR=1.13, 95%CI: 0.65-1.95, P=0.67). In conclusion, our results indicated that p-Akt was likely to be an indicator of poor prognosis in patients with gastric cancer.