Bo Wei

Eph receptors and ephrins as targets for cancer therapy

Eph receptor tyrosine kinases and their ephrin ligands are involved in various signalling pathways and mediate critical steps of a wide variety of physiological and pathological processes. Increasing experimental evidence demonstrates that both Eph receptor and ephrin ligands are overexpressed in a number of human tumours, and are associated with tumour growth, invasiveness and metastasis. In this regard, the Eph/ephrin system provides the foundation for potentially exciting new targets for anticancer therapies for Eph‐expressing tumours. The purpose of this review is to outline current advances in the role of Eph receptors and ephrin ligands in cancer, and to discuss novel therapeutic approaches of anticancer therapies.

A meta-analysis of robotic versus laparoscopic gastrectomy for gastric cancer

BackgroundRobot-assisted gastrectomy (RAG) for gastric cancer is still a controversial surgical technique for adequate tumor resection, lymphadenectomy, and postoperative outcome.MethodsA meta-analysis analyzed updated clinical trials that have compared RAG with laparoscopy-assisted gastrectomy (LAG) to evaluate whether RAG is equivalent to LAG.ResultsEight studies were included in the analysis, comprising 1,875 patients. RAG was associated with a longer operative time (pxa0<xa00.05), lower estimated blood loss (pxa0<xa00.05), and a longer distal margin (pxa0<xa00.05). RAG can be performed safely with lower estimated blood loss and a longer distal margin than with LAG. Complications, hospital stay, proximal margin, and harvested lymph nodes for RAG and LAG were similar.ConclusionsRAG is as acceptable as LAG for obtaining safe complications and for performing radical gastrectomy.

Aberrant expression of EphA3 in gastric carcinoma: correlation with tumor angiogenesis and survival.

BackgroundEphA3, a member of the Eph receptor tyrosine kinases, plays important roles in tumor angiogenesis and progression. However, the function of EphA3 in solid tumors has not been widely studied. We aimed to explore EphA3 expression in gastric carcinoma and analyze its role as a potential prognostic factor.MethodsQuantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess EphA3 mRNA in a normal gastric mucosa cell line and carcinoma cell lines. Immunohistochemistry for EphA3 and vascular endothelial growth factor (VEGF) was performed in 318 cases of gastric carcinoma. CD34 immunohistochemical staining was used for microvessel density (MVD) counting. Western blotting was used to analyze EphA3 expression in the cell lines and to determine the expression of EphA3 and VEGF in 75 cases of gastric carcinoma and matched normal mucosa.ResultsEphA3 mRNA and protein expression was significantly higher in gastric cancer than that in normal mucosa (all Pxa0<xa00.001). EphA3 was significantly correlated with TNM stage and poor prognosis (all Pxa0<xa00.001). Multivariate analysis showed that EphA3 had an independent effect on survival (Pxa0=xa00.037). EphA3 was positively correlated with VEGF (Pxa0<xa00.001), and MVD (Pxa0<xa00.001). According to Western blot analysis, both EphA3 and VEGF expression were significantly higher in carcinoma than that in normal mucosa (all Pxa0<xa00.001). A positive correlation was observed between EphA3 and VEGF expression in cancer (Pxa0<xa00.001, rxa0=xa00.513).ConclusionsEphA3 may play important roles in the angiogenesis and prognosis of gastric carcinoma, and thus may become a useful target for therapeutic intervention and a potential indicator for clinical assessment of tumor prognosis.

The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta-analysis

PurposeThe prognostic role of matrix metalloproteinase 2 (MMP-2) in gastric cancer remains controversial. We systematically reviewed the evidence for assessment of MMP-2 expression in gastric cancer to elucidate this issue.MethodPubmed, Embase and Web of Science were searched to identify eligible studies to evaluate the association of MMP-2 expression and overall survival and clinicopathological features of gastric cancer.ResultsMMP-2 overexpression was significantly correlated with poor OS of gastric cancer patients (HR 1.92, 95xa0% CI 1.48–2.48). Subgroup analysis indicated that MMP-2 overexpression had an unfavorable impact on OS in Asian countries (HR 2.23, 95xa0% CI 1.57–3.17) and European countries (HR 1.43, 95xa0% CI 1.13–1.80). Furthermore, MMP-2 overexpression was significantly associated with TNM stage (TIII/TIV vs TI/TII: OR 2.17, 95xa0% CI 1.64–2.87), the depth of invasion (T3/T4 vs T1/T2: OR 2.59, 95xa0% CI 1.63–4.12), lymph node metastasis (positive vs negative: OR 2.21, 95xa0% CI 1.69–2.88), and distant metastasis (positive vs negative: OR 4.44, 95xa0% CI 1.24–15.94).ConclusionThis meta-analysis indicated that MMP-2 overexpression might be a predictive factor for poor prognosis for gastric cancer.

Genome-Wide lncRNA Microarray Profiling Identifies Novel Circulating lncRNAs for Detection of Gastric Cancer.

Long non-coding RNAs (lncRNAs) can serve as blood-based biomarkers for cancer detection. To identify novel lncRNA biomarkers for gastric cancer (GC), we conducted, for the first time, genome-wide lncRNA screening analysis in two sets of samples: five paired preoperative and postoperative day 14 plasma samples from GC patients, and tissue samples from tumor and adjacent normal tissues. Candidate tumor-related lncRNAs were then quantitated and evaluated in three independent phases comprising 321 participants. The expression levels of lncRNAs were also measured in GC cell lines and the corresponding culture medium. Biomarker panels, lncRNA-based Index I and carcinoembryonic antigen (CEA)-based Index II, were constructed using logistic regression, and their diagnostic performance compared. Fagans nomogram was plotted to facilitate clinical application. As a result, we identified five novel plasma lncRNAs (TINCR, CCAT2, AOC4P, BANCR and LINC00857), which, when combined in the lncRNA-based Index I, outperformed the CEA-based Index II (P < 0.001) and could distinguish GC patients from healthy controls with an area under the receiver-operating curve (AUC) of 0.91 (95% confidence interval (CI): 0.88-0.95). The lncRNA-based index decreased significantly by postoperative day 14 (P = 0.016), indicating its ability to monitor tumor dynamics. High values of the lncRNA-based index were correlated with tumor size (P = 0.036), depth of invasion (P = 0.025), lymphatic metastasis (P = 0.012) and more advanced tumor stages (P = 0.003). The lncRNA-based index was also able to discriminate GC patients from precancerous individuals and patients with gastrointestinal stromal tumor with AUC values of 0.82 (95% CI: 0.71-0.92) and 0.80 (95% CI: 0.68-0.91), respectively. Taken together, our findings demonstrate that this panel of five plasma lncRNAs could serve as a set of novel diagnostic biomarkers for GC detection.

Decreased expression of Sox7 correlates with the upregulation of the Wnt/β-catenin signaling pathway and the poor survival of gastric cancer patients

Sox7 is a tumor suppressor gene that plays an important role in the inhibition and progression of cancer. In the present study, we sought to investigate Sox7 expression in gastric cancer (GC) and its association with the Wnt/β-catenin signaling pathway. We also wished to determine its clinicopathological significance and prognostic implications. Sox7 expression and its effects on the Wnt/β-catenin signaling in vitro were assessed by reverse transcription-polymerase chain reaction using the AGS, MKN-45 and GES-1 gastric cell lines. We also used immunohistochemistry on paraffin-embedded tissue samples and western blot analysis on fresh tissue samples from patients with GC. The results revealed that Sox7 expression was significantly lower in the GC samples than in distal normal tissues, which was in accordance with our results obtained from our in vitro experiments on the cell lines. However, the expression levels of β-catenin were significantly higher. Sox7 and β-catenin expression significantly correlated with the depth of invasion, lymph node metastasis, distant metastasis and the TNM stage. Patient samples that were Sox7-negative correlated with a significantly shorter survival time. Multivariate survival analysis revealed that Sox7 and β-catenin had an independent effect on the survival of GC patients. Sox7 and β-catenin expression in GC had a negative liner correlation with each other. Our findings suggest that Sox7 plays an important role in inhibiting tumorigenesis and progression, and may be a potential marker for predicting the prognosis of patients with GC.

Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis

The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. Periostin participates in normal physiological activities such as cardiac development, but is also involved in pathophysiological processes in vascular diseases, wound repair, bone formation, and tumor development. It is of increasing interest in tumor biology because it is frequently overexpressed in a variety of epithelial carcinomas and is functionally involved in multiple steps of metastasis progression. These include the maintenance of stemness, niche formation, EMT, the survival of tumor cells, and angiogenesis, all of which are indispensable for gastric cancer metastasis. Periostin has been reported to activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote metastasis. Therefore, periostin represents a potentially promising candidate for the inhibition of metastasis. In this review article, we summarize recent advances in knowledge concerning periostin, its antagonist PNDA-3, and their influence on such key processes in cancer metastasis as maintenance of stemness, niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and angiogenesis. In particular, we focus our attention on the role of periostin in gastric cancer metastasis, speculate as to the usefulness of periostin as a therapeutic and diagnostic target for gastric cancer metastasis, and consider potential avenues for future research.

Diagnostic and prognostic value of circulating tumor DNA in gastric cancer: a meta-analysis

Background Circulating tumor DNA (ctDNA) has offered a minimally invasive approach for detection and measurement of gastric cancer (GC). However, its diagnostic and prognostic value in gastric cancer still remains unclear. Results A total of 16 studies comprising 1193 GC patients met our inclusion criteria. The pooled sensitivity and specificity were 0.62 (95% confidence intervals (CI) 0.59−0.65) and 0.95 (95% CI 0.93–0.96), respectively. The AUSROC (area under SROC) curve was 0.94 (95% CI 0.89–0.98). The results showed that the presence of certain ctDNA markers was associated with larger tumor size (OR: 0.26, 95% CI 0.11–0.61, p = 0.002), TNM stage (I + II/III + IV, OR: 0.11, 95% CI 0.07−0.17, p = 0.000), as well as H. pylori infection. (H.p negative/H.p positive, OR: 0.57, 95% CI 0.36–0.91, p = 0.018). Moreover, there was also a significant association between the presence of ctDNA and worse overall survival (HR 1.77, 95% CI 1.38−2.28, p < 0.001), as well as disease-free survival (HR 4.36, 95% CI 3.08−6.16, p < 0.001). Materials and Methods Pubmed, Embase, Cochrane Library and Web of Science databases were searched for relating literature published up until November 30, 2016. Diagnostic accuracy variables were pooled by the Meta-Disc software. Engauge Digitizer and Stata software were applied for prognostic data extraction and analysis. Conclusions Our meta-analysis indicates the detection of certain ctDNA targets is significantly associated with poor prognosis of GC patients, with high specificity and relatively moderate sensitivity.

Robotic versus laparoscopic gastrectomy for gastric cancer: comparison of short-term surgical outcomes

AbstractBackgroundnRobot-assisted gastrectomy (RAG) is a new minimally invasive surgical technique for gastric cancer. This study was designed to compare RAG with laparoscopy-assisted gastrectomy (LAG) in short-term surgical outcomes.MethodsnBetween October 2011 and August 2014, 423 patients underwent robotic or laparoscopic gastrectomy for gastric cancer: 93 RAG and 330 LAG. We performed a comparative analysis between RAG group and LAG group for clinicopathological characteristics and short-term surgical outcomes.ResultsRAG was associated with a longer operative time (Pxa0<xa00.001), lower blood loss (Pxa0=xa00.001), and more harvested lymph nodes (Pxa0=xa00.047). Only three patients in LAG group had positive margins, and R0 resection rate for RAG and LAG was similar (Pxa0=xa00.823). The RAG group had postoperative complications of 9.8xa0%, comparable with those of the LAG group (Pxa0=xa00.927). Proximal margin, distal margin, hospital stay, days of first flatus, and days of eating liquid diet for RAG and LAG were similar. In the subgroup of serosa-negative patients, RAG had a longer operation time (Pxa0=xa00.003), less intraoperative blood loss (Pxa0=xa00.005), and more harvested lymph nodes (Pxa0=xa00.04). However, in the subgroup of serosa-positive patients, RAG had a longer operation time (Pxa0=xa00.001), but no less intraoperative blood loss (Pxa0=xa00.139) and no more harvested lymph nodes (Pxa0=xa00.139). Similarly, in the subgroup of total gastrectomy patients, RAG had a longer operation time (Pxa0=xa00.018), but no less intraoperative blood loss (Pxa0=xa00.173).ConclusionsThe comparative study demonstrates that RAG is as acceptable as LAG in terms of surgical and oncologic outcomes. With lower estimated blood loss, acceptable complications, and radical resection, RAG is a promising approach for the treatment of gastric cancer. However, the indication of patients for RAG is critical.

Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

The prognosis of gastric cancer remains poor due to clinical drug resistance. Novel drugs are urgently needed. Shikonin (SHK), a natural naphthoquinone, has been reported to trigger cell death and overcome drug resistance in anti-tumour therapy. In this study, we investigated the effectiveness and molecular mechanisms of SHK in treatment with gastric cancer. In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells. SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis. We confirmed that SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade, but also in a caspase-independent manner which mediates the nuclear translocation of apoptosis-inducing factor and Endonuclease G. Furthermore, we demonstrated that SHK enhanced the chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin in vitro and in vivo. Taken together, our data show that SHK may be a novel therapeutic agent in the clinical treatment of gastric cancer.