Linbo Wang

Prognostic improvement of reexcision for positive resection margins in patients with advanced gastric cancer.

AIMnThe aim of this study was to investigate the effect of reexcision for advanced gastric cancer (GC) with positive resection margins on prognosis and to identify the selection criteria for the reexcision of patients with positive margins.nnnPATIENTS AND METHODSnThis was a retrospective study of 122 patients with positive margins who underwent potentially curative resection for locally advanced GC. The clinicopathological factors and survival among 50 patients who were reexcised to a negative resection margin (NR group) and 72 patients who were left with a positive resection margin (PR group) were compared using univariate and multivariate analyses.nnnRESULTSnMedian survival in the PR group was 18 months compared with 23 months in the NR group (p = 0.019). In the ≤ pN2-category subset, the PR group had a significantly worse prognosis compared with the NR group (median survival of 25 months vs. 44 months; p = 0.021). This difference was not observed in the pN3-category subset. In the univariate analysis, variables including pTNM stage, pN-category, and positive resection margin had adverse effects on OS among the entire population of 122 patients. A positive margin was confirmed as an independent prognostic factor for OS in the multivariate analysis.nnnCONCLUSIONSnThe reexcision of a positive margin improves the prognosis of patients with advanced GC, especially in those paitents with ≤ pN2-category disease and in patients undergoing D2 lymphadenectomy. Obtaining routine frozen sections of samples from the resection margin should be mandatory in the treatment of all GC patients undergoing potentially curative surgery.

FOLFOX versus EOX as a neoadjuvant chemotherapy regimen for patients with advanced gastric cancer

Neoadjuvant chemotherapy is the preferred treatment of advanced gastric cancer. However, the choice of an optimal regimen remains controversial. The present study aimed to assess the effectiveness of preoperative chemotherapy with EOX and FOLFOX in Chinese patients with advanced gastric cancer. A total of 87 and 26 patients underwent FOLFOX and EOX regimens, respectively, for advanced gastric cancer between July 2004 and September 2012. Clinicopathological characteristics, pathological T stage, N stage and pathological response to tumour regression were retrospectively compared between the two groups. Following neoadjuvant chemotherapy, a higher number of patients manifested deeper invasive cancer in the FOLFOX group than those in the EOX group (P=0.047). In addition, a higher number of patients also exhibited metastatic lymph nodes in the FOLFOX group (67.8%) than in the EOX group (57.7%) (P=0.000). In the FOLFOX and EOX groups, 4 (4.6%) and 3 (11.5%) cases of complete regression were observed, respectively. A higher number of patients (38.5%) also exhibited tumour regression grades of 3 and 4 in the EOX group than in the FOLFOX group (19.5%) (P=0.047). Results of the present study suggest that the EOX regimen may be more effective than the FOLFOX regimen as preoperative chemotherapy for Chinese patients with advanced gastric cancer. The EOX regimen may be suitable for younger patients subjected to individual neoadjuvant chemotherapy.

miR-944 inhibits metastasis of gastric cancer by preventing the epithelial–mesenchymal transition via MACC1/Met/AKT signaling

MicroRNAs (miRNAs) are reported to play vital roles in tumor progression. Recently, miR‐944 was reported to play either an oncogenic or tumor suppressive role in human cancers. However, the expression of miR‐944 and its exact role in gastric cancer (GC) remain unknown. This study aimed to evaluate whether loss of miR‐944 could promote the epithelial–mesenchymal transition (EMT) of GC. Reduced expression of miR‐944 was identified in 40 pairs of human GC and matched normal tissues by qRT‐PCR. Reduced expression of mi‐944 was also observed in GC cell lines. Restoration of miR‐944 inhibited cell migration and invasion in MGC‐803 cells, while its loss facilitated metastasis of SGC‐7901 and BGC‐823 cells. Notably, miR‐944 overexpression prohibited EMT of GC cells in vitro, while miR‐944 knockdown had the opposite effect. Bioinformatics software predicted that MACC1 was a direct target of miR‐944. We observed negative regulation of miR‐944 on MACC1 expression, and direct binding between miR‐944 and MACC1 was verified by dual‐luciferase assays in HEK293T cells. Restoration of MACC1 resulted in promoted EMT and metastasis in miR‐944‐overexpressing MGC‐803 cells. Loss of MACC1 abrogated the effects of miR‐944 knockdown on EMT and metastasis of SGC‐7901 cells. We also found that the Met–AKT pathway might be involved in MACC1‐mediated EMT. In conclusion, miR‐944 acts as an inhibitor of EMT and metastasis of GC by targeting MACC1. This study highlights the potential effects of miR‐944 in the prognosis and treatment of GC.

KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer

Tamoxifen resistance represents a daunting challenge to the successful treatment for breast cancer. Krüppel-like factor 4 has critical roles in the development and progression of breast cancer, but its expression, function and regulation in the efficacy of TAM therapy in breast cancer have yet to be investigated. Here, we examined the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 correlated with increased TAM sensitivity in breast cancer cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ERα and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness to TAM in T47D and TAM-resistant MCF-7/TAM cells. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion and migration. Moreover, KLF4 expression was down-regulated in breast cancer tumor tissues and high expression of KLF4 was associated with favorable outcomes. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and p38 were more activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors significantly suppressed cell viability. Knockdown of KLF4 activated ERK and p38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and p38 signaling and resulted in increased sensitivity to TAM. Therefore, our findings suggested that KLF4 contributed to TAM sensitivity in breast cancer via phosphorylation modification of ERK and p38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for the TAM-resistant patients.

Laparoscopic surgery versus open resection in patients with gastrointestinal stromal tumors: An updated systematic review and meta-analysis

PURPOSESnThe contemporary surgery has reported the safety of laparoscopic surgery (LAP) for patients with gastrointestinal stromal tumors (GISTs). However, its use is still debated due to suspicion of the oncologic equivalence to open surgery (OPEN). We conducted a systematic review and meta-analysis of updated original articles to investigate the short- and long-term clinical outcomes of LAP compared with OPEN for GISTs.nnnMETHODSnA systematic search was performed in PubMed, Embase, Web of Science, Cochrane Library and CNKI. Comparative studies of laparoscopic and open surgery for GISTs were published before November 2016. The Newcastle-Ottawa scale was utilized to conduct quality assessment. The Review Manager (RevMan) software version 5.0 was used for meta-analysis.nnnRESULTSnTwenty-four studies involving 2140 patients were included for the meta-analysis. The meta-analysis results showed that, compared with OPEN, LAP indicated potentially favorable outcomes in terms of operative time (WMD,xa0-30.71; 95% CI,xa0-58.48 toxa0-2.95; Pxa0=xa00.03); intraoperative blood loss (WMD,xa0-60.90; 95% CI,xa0-91.53 toxa0-30.28; Pxa0<xa00.0001); time to flatus (WMD,xa0-1.10; 95% CI,xa0-1.41 toxa0-0.79; Pxa0<xa00.00001); time to oral intake (WMD,xa0-1.25; 95% CI,xa0-1.64 toxa0-0.86; Pxa0<xa00.00001); length of hospital stay (WMD,xa0-3.42; 95% CI,xa0-4.37 toxa0-2.46; Pxa0<xa00.00001); overall complications (OR, 0.38; 95% CI, 0.27 to 0.54; Pxa0<xa00.00001); and recurrence (OR, 0.45; 95% CI, 0.30 to 0.66; Pxa0<xa00.0001).nnnCONCLUSIONSnLaparoscopic surgery is safe and feasible for the treatment of GISTs including less operative time and intraoperative blood loss, earlier postoperative recovery, shorter hospital stay, and lower rate of overall complications and recurrence.

The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth

Accumulating evidence suggests that placenta-specific 8 (PLAC8) plays an important role in normal cellular process and human diseases, including multiple types of human tumors, and its role is highly relied upon in cellular and physiologic contexts. However, there are no reports on its expression profile and biological roles during lung cancer development. In the current study, both the clinical implications and biological effects of PLAC8 in lung cancer (LC) progression were investigated, and we identified and described the novel Krüppel-like factor 4 (KLF4)/PLAC8 regulatory pathway in cancer progression. Elevated PLAC8 levels were positively correlated with tumor size, histological grade, and tumor node metasis (TNM) stage, and LC patients with high PLAC8 expression suffered poor outcomes. In vitro and in vivo assays further revealed that endogenous PLAC8 promoted cell proliferation and tumor formation. We also found downregulated PLAC8 protein in several LC cell lines following the induction of KLF4, and immunohistochemistry analysis of LC tissues by microarray indicated a potential inverse correlation between PLAC8 and KLF4 expression. Luciferase reporter analysis and chromatin immunoprecipitation assays determined that KLF4 negatively regulated PLAC8 promoter activity via directly binding to the promoter region. Furthermore, the growth inhibition resulting from KLF4 overexpression was partially rescued by ectopic PLAC8 expression. Together, our data uncovered a previously unidentified role of PLAC8 as a central mediator in LC progression. PLAC8 was transcriptionally repressed by KLF4, and the novel KLF4/PLAC8 axis may act as a promising candidate target for LC diagnosis and therapy.