KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1-PDK1-AKT signaling pathway.

Kirsten rat sarcoma virus (KRAS) gene mutation is common in colorectal cancer (CRC) and is often predictive of treatment failure and poor prognosis. To understand the mechanism, we compared the transcriptome of CRC patients with wild-type and mutant KRAS and found that KRAS mutation is associated with the overexpression of a secreted serine protease, kallikrein-related peptidase 10 (KLK10). Moreover, using in vitro and in vivo models, we found that KLK10 overexpression favors the rapid growth and liver metastasis of KRAS mutant CRC and can also impair the efficacy of KRAS inhibitors, leading to drug resistance and poor survival. Further functional assays revealed that the oncogenic role of KLK10 is mediated by protease-activated receptor 1 (PAR1). KLK10 cleaves and activates PAR1, which further activates 3-phosphoinositide-dependent kinase 1 (PDK1)-AKT oncogenic pathway. Notably, suppressing PAR1-PDK1-AKT cascade via KLK10 knockdown can effectively inhibit CRC progression and improve the sensitivity to KRAS inhibitor, providing a promising therapeutic strategy. Taken together, our study showed that KLK10 promotes the progression of KRAS mutant CRC via activating PAR1-PDK1-AKT signaling pathway. These findings expanded our knowledge of CRC development, especially in the setting of KRAS mutation, and also provided novel targets for clinical intervention.

Copy number variants landscape of multiple cancers and clinical applications based on NGS gene panel.

BACKGROUND: The rapid adoption of next-generation sequencing in clinical oncology has enabled detection of molecular biomarkers which are shared between multiple tumour types. Intra-tumour heterogeneity is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the tumour-related copy number variants (CNVs), as key regulators of cancer origination, development, and progression, across various types of cancers are poorly understood. METHODS: We performed pan-cancer CNV analysis of cancer-related genes in 15 types of cancers including 1438 cancerous patients by next-generation sequencing using a commercially available pan-cancer panel (Onco PanScan™). Downstream bioinformatics analysis was performed in order to detect CNVs, cluster analysis of the found CNVs, and comparison of the frequency of gained CNVs between different types of cancers. LASSO analysis was used for identification of the most important CNVs. RESULTS: We also identified 523 CNVs among which 16 CNVs were common while 22 CNVs were caner-specific CNVs. Meanwhile, FAM58A was most commonly found in all studied cancers in this study and significant differences were found in FAM58A between female and male patients (p = .001). Common CNVs, such as FOXA1, NFKBIA, HEY1, MECOM, CHD7, AGO2, were mutated in 6.79%, 8.45%, 7.51%, 6.43%, 7.59%, 8.16% of tumours, while most of these mutations have proven roles in positive regulation of transcription from RNA polymerase II promoter. 11 features including sex, DIS3, EPHB1, ERBB2, FLT1, HCK, KEAP1, MYD88, PARP3, TBX3, and TOP2A were found as the key features for classification of cancers using CNVs. CONCLUSION: The 16 common CNVs between cancers can be used to identify the target of pan-cancer drug design and targeted therapies. Additionally, 22 caner-specific CNVs can be used as unique diagnostic markers for each cancer type.

Novel biosynthesis of gold nanoparticles for multifunctional applications: Electrochemical detection of hydrazine and treatment of gastric cancer.

In this work, an environmentally friendly strategy was used to synthesize gold nanoparticles (Au NPs) using Olea europaea (olive) fruit. Transmission electron microscopy (TEM), UV-Vis spectroscopy, X-ray diffraction (XRD) and energy-dispersive X-ray (EDX) were used to characterize the physicochemical properties of the synthesized NPs. An Au NPs modified glassy carbon electrode was used to investigate the direct electrochemical oxidation of hydrazine. The suggested hydrazine sensor has good performance, such as a wide linear range (2.5-275 µM), low limit of detection (0.09 µM), notable selectivity and excellent reproducibility (RSD = 2.2%). The in-vitro cytotoxicity of three human cancer cell lines (KATOIII, NCI-N87, and SNU-16) was also explored with various concentrations of Au NPs prepared from olive fruit extract. Bio-synthesized Au NPs were found to have cytotoxic properties against gastric cancer in humans based on MTT assay protocol. The obtained results show that green synthesized Au NPs can be successfully employed in electrochemical sensing and cancer treatment applications.

Efficacy of postoperative intraperitoneal hyperthermic perfusion chemotherapy with oxaliplatin + 5-Fluorouracil in the treatment of gastric cancer patients with peritoneal carcinomatosis.

PURPOSE: To explore the effect of palliative laparoscopic resection of gastric cancer combined with intraperitoneal hyperthermic perfusion chemotherapy (IHPC) with oxaliplatin + 5-fluorouracil (5-FU) on gastric cancer patients with peritoneal carcinomatosis (PC). METHODS: 90 patients definitely diagnosed with gastric adenocarcinoma and PC and admitted to our hospital from March 2013 to March 2016 were collected and divided into IHPC group (n=45) and control group (n=45). In IHPC group, IHPC with oxaliplatin + 5-FU was carried out for the first time on the first day after operation, and then it was conducted once every other day for a total of 4 times. The clinical efficacy, quality of life, adverse reactions, postoperative tumor recurrence and survival of the patients were observed and recorded. RESULTS: The total effective rates in IHPC group and control group were 62.2% (28/45) and 55.6% (25/45), respectively (p>0.05). In both groups, the curative effect was the best in moderately differentiated adenocarcinoma and worst in signet ring cell carcinoma. Besides, the effective rates of Karnofsky performance status (KPS) in the two groups after operation were 82.2% (37/45) and 75.6% (34/45), respectively (p=0.606). However, the renal function indexes, serum creatinine (sCr) and blood urea nitrogen (BUN) in the two groups of patients after operation were increased, and those in the IHPC group were higher than those in the control group (p=0.016, p=0.010). Moreover, follow-up results of patients' survival revealed that the OS and PFS in the IHPC group were significantly higher than those in the control group (p=0.041, p=0.045). CONCLUSIONS: Palliative laparoscopic resection of gastric cancer combined with IHPC with oxaliplatin +5-FU has a definite therapeutic effect on gastric cancer with PC, which can achieve a better short-term clinical therapeutic effect and better postoperative quality of life.

Impact of PSCA gene polymorphisms in modulating gastric cancer risk in the Chinese population.

Previous studies have identified the prostate stem cell antigen (PSCA) gene rs2294008 C > T and rs2976392 G > A polymorphisms to be associated with the risk of gastric cancer, the results of which are inconsistent. The present study aimed to evaluate the association between the two polymorphisms and the gastric cancer risk in the Chinese population. A hospital-based case-control study was conducted on 549 cases and 592 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the association of the two polymorphisms on the gastric cancer risk. We found that both rs2294008 (CT vs. CC, OR = 1.55, 95% CI = 1.20-1.99, P<0.001 and CT+TT vs. CC, OR = 1.38, 95% CI = 1.09-1.74, P=0.008) and rs2976392 (GA vs. GG, OR = 1.61, 95% CI = 1.25-2.07, P<0.001 and GA+AA vs. GG, OR = 1.52, 95% CI = 1.20-1.92, P<0.001) were associated with an increased gastric cancer. In the combined analysis of the two polymorphisms, subjects with more than one risk genotype have a significantly increased risk of gastric cancer (OR = 1.38, 95% CI = 1.09-1.75, P=0.008) in comparison with those without any risk genotypes. In conclusion, our findings verified that the PSCA gene rs2294008 and rs2976392 polymorphisms were both significantly associated with an increased risk of gastric cancer in the Chinese population. Well-designed functional studies are to be warranted to confirm these findings.