Both transforming growth factor-β (TGF-β) and parathyroid hormone-related protein (PTHrP) regulate important cellular processes, such as apoptosis in the development of hepatocellular carcinoma. However, the mechanisms of regulation of PTHrP by TGF-β are largely unknown. We hypothesized that TGF-β regulates the expression of PTHrP protein through a post-translational mechanism. Using hepatocellular carcinoma cell lines as the in vitro model, we investigated the effects of TGF-β on protein expression and post-translational processing of PTHrP. We found that TGF-β treatment led to protein degradation of PTHrP through the ubiquitin-proteasome-dependent pathway. We also provided evidence to show that Smurf2 was the E3 ligase responsible for the ubiquitination of PTHrP. Furthermore, using immunohistochemistry on human hepatocellular carcinoma specimens and a tissue array, we found that the expression of PTHrP was predominantly in the cancer cells, whereas the expression of TGF-β was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-β may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-β in hepatocellular carcinoma may promote cancer progression. Promotion of PTHrP degradation provides a novel target of therapeutic intervention to sensitize hepatocellular carcinoma cells to cytostatic and/or pro-apoptotic signals.

Objective: To explore the anti-tumor effect of FIN56, a novel ferroptosis inducer, on glioblastoma and its underlying mechanisms. Methods: Two human glioblastoma cell lines, LN229 and U118 were applied in this study. Anti-tumor effect was measured by CCK-8 assay, EdU assay and cell cycle analysis. Fluorescent probes, immunofluorescence, plasmid transfection, shRNA knocking out, reverse transcription PCR, western blot analysis, and transmission electron microscopy were used to study the underlying mechanisms. At last, a subcutaneous nude mice model was used to study the anti-tumor effect of FIN56 in vivo. The GraphPad Prism software program was applied for statistical analysis. Results: FIN56 decreased cell viability, inhibited cell proliferation and caused cell cycle arrest on LN229 and U118 cells. Further study showed that FIN56 induced ferroptosis and induced lysosomal membrane permeabilization in a ferroptosis and transfactor EB dependent manner. Animal study demonstrated that FIN56 inhibited glioma growth and caused ferroptosis in vivo. Conclusion: FIN56 is a promising anti-tumor compound.

Background: The promoter methylation of MLH1 gene and gastric cancer (GC)has been investigated previously. To get a more credible conclusion, we performed a systematic review and meta and bioinformatic analysis to clarify the role of MLH1 methylation in the prediction and prognosis of GC. Methods: Eligible studies were targeted after searching the PubMed, Web of Science, Embase, BIOSIS, CNKI and Wanfang Data to collect the information of MLH1 methylation and GC. The link strength between the two was estimated by odds ratio with its 95% confidence interval. The Newcastle-Ottawa scale was used for quantity assessment. Subgroup and sensitivity analysis were conducted to explore sources of heterogeneity. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were employed for bioinformatics analysis on the correlation between MLH1 methylation and GC risk, clinicopathological behavior as well as prognosis. Results: 2365 GC and 1563 controls were included in the meta-analysis. The pooled OR of MLH1 methylation in GC was 4.895 (95% CI: 3.149-7.611, P<0.001), which considerably associated with increased GC risk. No significant difference was found in relation to Lauren classification, tumor invasion, lymph node/distant metastasis and tumor stage in GC. Analysis based on GEO and TCGA showed that high MLH1 methylation enhanced GC risk but might not related with GC clinicopathological features and prognosis. Conclusion:MLH1 methylation is an alive biomarker for the prediction of GC and it might not affect GC behavior. Further study could be conducted to verify the impact of MLH1 methylation on GC prognosis.

Minichromosome maintenance proteins (MCM) played a critical role in replication and cell cycle progression. However, their prognostic roles in cancer remain controversial. Therefore, we performed a meta-analysis to investigate the prognostic value of MCMs in cancers. Totally 31 eligible articles with 7653 cancer patients were included in this meta-analysis. We evaluated the relationship between MCMs expression and overall survival (OS) in various cancer patients by using pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs). The meta-analysis showed that carriers with high expression of MCM5 and MCM7 were significantly associated with short OS for pooled HR (HR=1.04, 95% CI=1.01-1.08, P=0.020, HR=1.78, 95% CI=1.04-3.02, P=0.035, respectively). For pooled RR, individuals with increased MCM2 and MCM7 expression were significantly correlated with poor OS (RR=2.30, 95% CI=1.14-4.63, P=0.019; RR=3.52, 95% CI=2.01-6.18, P<0.001, respectively). The findings suggest that high expression of MCM2, MCM5 and MCM7 might serve as predictive biomarkers for poor prognosis in cancers.

Introduction: SRPX2 and RAB31 play important roles in tumorigenesis and metastasis; however, their prognostic value in pancreatic cancer remains unclear. This study aimed to investigate the potential interactions and effects of SRPX2 and RAB31 on the diagnosis and prognosis of pancreatic cancer. Methods: The expression of SRPX2 and RAB31 in pancreatic tumor tissues and cells was evaluated through database mining of the Oncomine, Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and validated the results through immunohistochemistry (IHC) and Western blot in our clinical database. Protein-protein interactions were explored by immunofluorescence and Co-immunoprecipitation (Co-IP). Two hundred tissue microarray specimens from patients (79 training and 121 validation), who underwent curative pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) were used. Additionally, the association between the SRPX2 and RAB31 and prognosis of PDAC patients after surgery was analyzed. Results: The expression of SRPX2 and RAB31 was highly increased in pancreatic cancer, and there was a significant positive correlation between these two proteins. Co-IP showed the direct interaction between SRPX2 and RAB31. Kaplan-Meier analysis showed that positive expression of SRPX2 and RAB31 was associated with reduced disease-free survival (DFS) and overall survival (OS) of PDAC patients in the training set and the validation sets. Furthermore, multivariate analysis indicated that the 8th edition TNM stage and combination of SRPX2 and RAB31 were independent prognostic factors that associated with OS and DFS in the training, and the validation sets, respectively. Conclusions: The combination of SRPX2 and RAB31 can be important markers for the prognosis of pancreatic cancer.

Background: Emerging evidence suggested that aberrant alternative splicing (AS) is pervasive event in development and progression of cancer. However, the information of aberrant splicing events involved in colorectal carcinogenesis and progression is still elusive. Materials and Methods: In this study, splicing data of 499 colon adenocarcinoma cases (COAD) and 176 rectum adenocarcinoma (READ) with clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) to explore the changes of alternative splicing events in relation to the carcinogenesis and prognosis of colorectal cancer (CRC). Gene interaction network construction, functional and pathway enrichment analysis were performed by multiple bioinformatics tools. Results: Overall, most AS patterns were more active in CRC tissues than adjacent normal ones. We detected altogether 35391 AS events of 9084 genes in COAD and 34900 AS events of 9032 genes in READ, some of which were differentially spliced between cancer tissues and normal tissues including genes of SULT1A2, CALD1, DTNA, COL12A1 and TTLL12. Differentially spliced genes were enriched in biological process including muscle organ development, cytoskeleton organization, actin cytoskeleton organization, biological adhesion, and cell adhesion. The integrated predictor model of COAD showed an AUC of 0.805 (sensitivity: 0.734; specificity: 0.756) while READ predictor had an AUC of 0.738 (sensitivity: 0.614; specificity: 0.900). In addition, a number of prognosis-associated AS events were discovered, including genes of PSMD2, NOL8, ALDH4A1, SLC10A7 and PPAT. Conclusion: We draw comprehensive profiles of alternative splicing events in the carcinogenesis and prognosis of CRC. The interaction network and functional connections were constructed to elucidate the underlying mechanisms of alternative splicing in CRC.

Objectives: To investigate the effect of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer in terms of pCR and cardiotoxicity. Methods: We systematically searched Pubmed, Embase, Cochrane and SinoMed databases from inception until 1 July 2017 for relevant articles of randomized controlled studies. After identified all relevant studies that reported the concurrent use of trastuzumab and anthracycline-based NAC for HER2-positive locally advanced breast cancer, five eligible randomized studies were extracted relevant data and assessed for design and quality, and the meta-analysis was conducted to evaluate the risk ratio (RR) of pCR and other interesting outcomes, such as left ventricular ejection fraction (LVEF) decrease more than 10%, responses, recurrence free survival (RFS) and overall survival (OS). Results: A total of five randomized controlled studies were included in the meta-analysis, including 232 HER2-positive locally advanced breast cancer patients received the concurrent use of trastuzumab and anthracycline-based NAC. The results showed that the pCR rate was significantly higher in the group received the concurrent use of trastuzumab and anthracycline-based NAC (48%) than that in the non-concurrent use of trastuzumab and anthracycline-based NAC group (26%) (RR: 1.76, 95%CI: 1.37-2.26, p<0.0001). Besides, higher rate of RFS (RR: 1.14, 95%CI: 1.03-1.26, p=0.009) was observed in the concurrent use of trastuzumab and anthracycline-based NAC group. No significant differences in LVEF decreased more than 10% (p=0.50) between both groups. Conclusions: Our meta-analysis of randomized controlled studies showed that pCR rates are significantly higher in the concurrent use of trastuzumab and anthracycline-based NAC compared with the non-concurrent use of trastuzumab and anthracycline-based NAC for certain HER2-positive breast cancer, meanwhile without significant increase of the cardiotoxicity.

Background: The molecular function of pannexin1 (Panx1) in different tumor types has been remained equivocal. Until now, there is no study focused on the function of panx1 in hepatocellular carcinoma (HCC). This study aimed to explore the role of Panx1 in the invasion and metastasis of HCC. Methods: The expressions of Panx1 in 126 cases of HCC were analyzed by immunohistochemistry (IHC). The effects of Panx1 on HCC cell metastasis and invasion were observed by transwell. The expression levels of Panx1 and epithelial-mesenchymal transition (EMT) related proteins in HCC cells and tissues were detected by western blot and IHC. The tumor metastatic abilities were compared between Panx1 knockout mice and nude mice. Results: The higher expression of Panx1 in HCC was positively correlated with tumor lymph node metastasis, TNM (tumor, node, metastasis) classification and poor prognosis (overall survival, hazard ratio [HR] 2.769, 95% confidence interval [95%CI] 1.528-5.017, P=0.001; disease-free survival, HR=2.344, 95%CI 1.473-3.730, P<0.001). Overexpression of Panx1 promoted invasion and migration of HCC cells through modulation of EMT in vitro and in vivo. Conclusions: Our results suggest that the high expression of Panx1 is associated with poor HCC prognosis, providing a new clue for effective intervention for HCC metastasis.

Purpose: Several studies have indicated that SLC39A7 plays an important role in tumor progression; however, little is known about the function and mechanism of SLC39A7 in glioma. In this study, we aimed to explore the role of SLC39A7 in glioma development. Patients and methods: Bioinformatic analysis was used to predict the role of SLC39A7 in glioma. Cell viability and Edu assays were used to detect the proliferation of glioma cells. A transwell assay was used to measure the invasion and migration of glioma cells. Western blotting, qPCR and ELISA were used to detect the expression of all molecules. Results: SLC39A7 was found to be highly expressed in high-grade glioma patients with a poor prognosis. Our results indicated that SLC39A7 significantly promoted the proliferation, invasion and migration of glioma cells. Furthermore, SLC39A7 promoted tumorigenesis in orthotopic models. We determined that SLC39A7 promotes the malignant behaviors of glioma by activating the TNF-α-mediated NF-κB signaling pathway. Conclusion: Our study revealed that SLC39A7 promotes the proliferation, invasion and migration of glioma cells via the TNF-α-mediated NF-κB signaling pathway, which provides potential targets for glioma therapy.