Upregulated expression of long non-coding RNA LINC00982 regulates cell proliferation and its clinical relevance in patients with gastric cancer.

Emerging evidences indicate that dysregulated long non-coding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be used as diagnosis and prognosis biomarker or potential therapeutic targets. Therefore, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. In this study, we identified a novel lncRNA LINC00982, whose expression was downregulated in tumor tissues in 106 patients with gastric cancer (GC) compared with those in the adjacent normal tissues (P < 0.001). Furthermore, decreased LINC00982 expression was negatively correlated with invasion depth (P < 0.001), advanced TNM stage (P = 0.004), and regional lymph node metastasis (P = 0.005). LINC00982 levels were robust in differentiating gastric cancer tissues from controls [area under the curve (AUC) = 0.742; 95 % confidence interval (CI) = 0.678-0.800, P < 0.01]. Kaplan-Meier analysis demonstrated that decreased LINC00982 expression contributed to poor overall survival (P < 0.01) and disease-free survival (P < 0.01) of patients. A multivariate survival analysis also indicated that LINC00982 could be an independent prognostic marker. The levels of LINC00982 in gastric juice from gastric patients were significantly lower than those from normal subjects (P = 0.026). Furthermore, knockdown of LINC00982 expression by small interfering RNA (siRNA) could promote cell proliferation and cell cycle progression, while ectopic expression of LINC00982 inhibited cell proliferation and rendered cell cycle arrest in GC cells partly via regulating P15 and P16 protein expressions. Our findings present that decreased lncRNA LINC00982 could be identified as a poor prognostic biomarker in GC and regulate cell proliferation.

Upregulated expression of long noncoding RNA SNHG15 promotes cell proliferation and invasion through regulates MMP2/MMP9 in patients with GC.

Accumulation of data indicates that misregulated long noncoding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be served as diagnosis and prognosis biomarker or potential therapeutic targets. Identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are significant for understanding the development and progression of cancer. In this study, we identified a novel lncRNA SNHG15, whose expression was upregulated in tumor tissues in 106 patients with gastric cancer (GC) compared with those in the adjacent normal tissues (P < 0.001). Furthermore, increased SNHG15 expression was positively correlated with invasion depth (P < 0.001), advanced tumor node metastasis (TNM) stage (P = 0.001), and lymph node metastasis (P = 0.019). SNHG15 levels were robust in differentiating GC tissues from controls (area under the curve (AUC) = 0.722; 95 % confidence interval (CI) = 0.657-0.782, P < 0.01). Kaplan-Meier analysis demonstrated that elevated SNHG15 expression contributed to poor overall survival (P < 0.01) and disease-free survival (P < 0.01) of patients. A multivariate survival analysis also indicated that SNHG15 could be an independent prognostic marker. Furthermore, knockdown of SNHG15 expression by siRNA could inhibit cell proliferation and invasion and induce apoptosis, while ectopic expression of SNHG15 promoted cell proliferation and invasion in GC cells partly via regulating MMP2 and MMP9 protein expression. Our findings present that elevated lncRNA SNHG15 could be identified as a poor prognostic biomarker in GC and regulate cell invasion.

Benefit of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis.

We aimed to perform a meta-analysis to assess the impact of radiotherapy (RT) on both 3- and 5-year survival in patients with resectable gastric cancer. Relevant studies were identified by using PubMed, Embase and the Cochrane Controlled Trials Register through May 2013. We included randomized clinical trials (RCTs) that compared survival of surgery combined with RT (preoperative and/or postoperative) to surgery alone or surgery plus chemotherapy. Meta-analysis was performed using risk ratios (RRs). Both fixed- and random-effects models were used to calculate the summary risk estimates. Fourteen RCTs involving 2,853 participants were included in this meta-analysis. The addition of RT significantly increased the 3-year (RR 1.19; 95% confidence interval (CI) 1.05-1.35) and 5-year survival (RR 1.25; 95% CI 1.12-1.40). A significant advantage was also observed in subgroup analysis of preoperative RT for both 3-year (RR 1.56; 95% CI 1.19-2.05) and 5-year overall survival (RR 1.40; 95% CI 1.13-1.73). There was no evidence that preoperative RT increased postoperative mortality (RR 0.85; 95% CI 0.42-1.72). Surgery combined with RT or chemoradiotherapy compared to surgery alone improved the 3-year (RR 1.18; 95% CI 1.01-1.38) and 5-year survival rate (RR 1.38; 95% CI 1.18-1.61). Although the quality of the studies was variable, the data were consistent, and no substantial publication bias was observed. In patients with resectable gastric carcinoma, adjuvant RT significantly increased the 3-year and 5-year survival. Preoperative RT is safe and definitely improves overall survival. Available evidence is insufficient to determine the benefit of postoperative RT after an extended lymphadenectomy and radical resection.

Intraperitoneal recombinant human endostatin combined with chemotherapy for refractory malignant ascites due to gastrointestinal cancer: a pilot study.

BACKGROUND/AIMS: To evaluate the efficacy, safety and consequent impact on quality of life of a combined-modality using intraperitoneal recombinant human endostatin, Endostar and chemotherapy in patients with refractory malignant ascites caused by gastrointestinal cancer. METHODOLOGY: Patients received combined intraperitoneal therapy repeated 3 weeks, which consisted of 5-fluorouracil 600 mg/m2 and cisplatin 30 mg/m2 on day 1-3 followed by Endostar 60 mg on day 4. RESULTS: A total of 18 patients were treated. The overall response rate was 55.6%, with a complete remission rate of 22.2%. The malignant ascites controlled rate was 77.8%. The median time to progression and overall survival was 2.6 and 4.9 months, respectively. Therapy-associated toxicities were generally mild to moderate treatment-related deaths. The mean Karnofsky performance status score was significantly improved from 59.4±2.49 at enrollment to 69.4±3.18 at 2 weeks after the first cycle of therapy (p=0.001). The mean score for overall ascites-associated symptoms was improved from 5.3±0.35 to 4.0±0.23 (p=0.004). Significant improvements of 6 individual symptoms were also observed. CONCLUSIONS: The combined-modality using intraperitoneal Endostar and chemotherapy is effective and safe in selected patients with refractory malignant ascites due to gastrointestinal cancer and significantly improves patient's quality of life with encouraging survival, which merits further investigation.

[Expression profiles of microRNAs in radioresistant esophageal cell line].

OBJECTIVE: To identify the differential microRNA expression profiles of acquired radioresistant esophageal cell line established by fractionated ionizing radiation (FIR) versus parental cell line. METHODS: MicroRNA microarray was employed for detection. Bioinformatic software tools were used to predict the target genes of identified microRNAs. For an understanding of miRNA functions, the GO analysis of abundantly differentially expressed targets of miRNAs was performed by GeneOntology Browser. RESULTS: Compared with parental cell line, 10 microRNAs (hsa-miR-1539, hsa-miR-1237, hsa-miR-92b, etc.) were up-regulated over 2-fold and 25 microRNAs (hsa-miR-185, hsa-miR-18b, hsa-miR-17, etc.) down-regulated in KYSE-150R. Eighteen miRNAs had their target genes, 10 of them had the potential to individually target up to 200 mRNAs. Hsa-let-7a, hsa-miR-185, hsa-miR-141, hsa-miR-92b, hsa-miR-22 and hsa-miR-301a were known as important genes associated with radioresistance. CONCLUSION: These results confirm the involvement of miRNA in radiation resistance. It may potentially help to explain the mechanisms of gene regulation in cellular response to radioresistance.

[Protein microarray analysis on changes in protein phosphorylation in recurrent nasopharyngeal carcinoma].

OBJECTIVE: To compare the differential phosphorylation level of proteins between relapsed nasopharyngeal carcinoma (rNPC) and primary nasopharyngeal carcinoma (pNPC). METHODS: Total protein was extracted from 4 pNPC tissue and 4 rNPC tissue samples from January 2003 to September 2005. Then it was analyzed by antibody microarray with 656 antibodies. The differential phosphorylation level of proteins was screened and clustering analysis conducted. The phosphorylation status of the protein sites and its functional pathways were analyzed via an online database of PhosphoSite Plus. The protein expressions were detected by immunohistochemistry. RESULTS: Relapsed and primary nasopharyngeal carcinomas had differential phosphorylation level of proteins. And 6 differentially expressed proteins were identified. The phosphorylation levels of KIT, ATP1A1, Synapsin, SEK1 and histone H2AX were up-regulated in rNPC (P = 0.007 - 0.048) while c-Jun was down-regulated (P = 0.030). The expression of P-H2AX in rNPC was significantly higher than that in pNPC [0.390 (0.175) vs 0.290 (0.155)], but p-c-Jun was significantly lower in rNPC than that in pNPC [0.625 (0.145) vs 0.725 (0.178)] (both P < 0.05). Among them, the changes in the phosphorylation levels of c-Jun, histone H2AX, SEK1 and KIT might play important roles in the relapse of NPC through improving DNA damage repair ability, inhibiting apoptosis and promoting tumorigenesis. CONCLUSION: The changes of protein phosphorylation may help to explain the recurrent mechanisms of NPC and provide new therapeutic anti-recurrence targets.

[The effect on life quality of nasopharyngeal cancer patients through xerostomia decrease after intensity-modulated radiotherapy].

OBJECTIVE: To evaluate the gain on the life quality of NPC from efforts to reduce the radiotherapy-induced xerostomia after IMRT. METHODS: From August 2002 to December 2008, 235 patients with nasopharyngeal carcinoma were treated with IMRT in the First Affiliated Hospital of Wenzhou Medical College. Ninety-one patients with minimum 2 years of survival and no replaces and metastasis were enlisted. XQ and QOL questionnaires were completed at baseline, then 0, 3, 6, 9, 12, 18 and 24 months after IMRT. RESULTS: The XQ scores were substantially higher at the end of IMRT compared with baseline and descended over time. At 9 months post-RT, the XQ scores improved significantly (P = 0.024) and recovered nearly to baseline at 18 months post-RT. Likewise, the QOL scores were significantly higher at the end of IMRT compared with baseline (P = 0.012) and had a sequential trend towards improvement over the study period. At 18 months post-RT, the QOL scores almost recover to baseline (P = 0.020). Multiple comparisons testing revealed that communication, eating and pain sub-scale scores were significantly higher at the end of IMRT compared with baseline(P < 0.05) with the exception of emotion domain. There was a significant correlation between XQ scores and QOL scores in general in all the study time (r = 0.976, P < 0.001), also a significant position correlation was found between XQ scores and communication, eating sub-scale scores and overall bother scores. CONCLUSIONS: IMRT technique can reduce the incidence of postradiation xerostomia significantly and can improve the quality of life in many domains.

Retraction Note to: Decreased expression of the long noncoding RNA LINC00261 indicate poor prognosis in gastric cancer and suppress gastric cancer metastasis by affecting the epithelial-mesenchymal transition.

RETRACTION: The authors have retracted this article [1] because of significant overlap of text and some images with a previously published article by Xu et al. [2]. A formal investigation by the 1st Affiliated Hospital of Wenzhou Medical University has found that some panels in Fig. 6b [1] are identical with panels in Fig. 5a [2] and some images of mice lungs in Fig. 6c [1] are identical with images in Fig. 3g [2]. The data reported in this article are therefore unreliable. All authors agree to this retraction.

Decreased expression of the long noncoding RNA LINC00261 indicate poor prognosis in gastric cancer and suppress gastric cancer metastasis by affecting the epithelial-mesenchymal transition.

BACKGROUND: Recent evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in the regulation of cellular processes and are found to be dysregulated in a variety of cancers. LINC00261 is an lncRNA that is aberrantly expressed in gastric cancer (GC). The clinical role of LINC00261 in GC and molecular mechanisms remains to be found. METHODS: Real-time polymerase chain reaction (PCR) was used to examine LINC00261 expression in GC cell lines/tissues compared with normal epithelial cells/adjacent non-tumorous tissues. Gain and loss of function approaches were used to investigate the biological role of LINC00261 in GC cells. The effects of LINC00261 on cell viability were evaluated by MTT and colony formation assays. Wound healing assay, cell migration and invasion assays, and nude mice were used to examine the effects of LINC00261 on tumor cell metastasis in vitro and in vivo. Protein levels of LINC00261 targets were determined by western blot and immunohistochemistry. RESULTS: LINC00261 was downregulated in GC cell lines and cancerous tissues, as compared with normal gastric epithelial cells and adjacent noncancerous tissue samples. Low LINC00261 expression was correlated with deeper tumor invasion (P < 0.001), higher tumor stage (P = 0.013), and lymphatic metastasis (P = 0.006). Univariate and multivariate analyses indicated that low LINC00261 expression predicted poor prognosis. Ectopic expression of LINC00261 impaired cell migration and invasion, leading to the inhibition of metastasis in vitro and in vivo. Knockdown of LINC00261 expression promoted cell migration and invasion in vitro. Overexpression of LINC00261 was found to play a key role in epithelial-mesenchymal transition (EMT) through the regulation of E-cadherin, N-cadherin, and Vimentin expression. CONCLUSIONS: Low expression of the lncRNA LINC00261 occurs in GC and is associated with poor prognosis. LINC00261 suppresses GC metastasis by regulating EMT. Thus, LINC00261 plays an important role in the progression and metastasis of GC.

Association between single nucleotide polymorphisms of the transforming growth factor-ß1 gene and overall survival in unresectable locally advanced non-small-cell lung cancer patients treated with radio(chemo)therapy in a Chinese population.

The outcome is variable for unresectable locally advanced non-small-cell lung cancer (ULANSCLC) patients treated with radio(chemo)therapy. The aim of this study is to investigate whether single-nucleotide polymorphisms (SNPs) in the transforming growth factor-beta1 (TGF-ß1) gene are associated with overall survival (OS) in ULANSCLC patients treated with definitive radio(chemo)therapy. A total of 109 patients who had available blood samples and complete clinical and follow-up information were enrolled. DNA from blood was genotyped for two SNPs: TGF-ß1 C-509T and T+869C. Kaplan-Meier survival analysis, log-rank test, and Cox's proportional hazard model were used to evaluate associations between genotypes and OS. Log-rank test showed that TGF-ß1 C-509T significantly correlated with OS (pooled P = 0.017). Both univariate and multivariate analyses showed that TGF-ß1 C-509T CC genotype was significantly associated with better OS than CT or TT genotypes. These results indicate that TGF-ß1 C-509T CC genotype is significantly associated with better OS in ULANSCLC patients treated with radio(chemo)therapy as a potential independent survival predictor.

Simultaneous modulated accelerated radiation therapy and concurrent weekly Paclitaxel in the treatment of locally advanced nasopharyngeal carcinoma.

OBJECTIVES: To evaluate the feasibility and efficacy of simultaneous accelerated radiation therapy (SMART) and concurrent weekly paclitaxel in the treatment of locally advanced nasopharyngeal carcinoma. METHODS: Forty- one patients with pathologically confirmed nasopharyngeal carcinoma were treated by SMART with concurrent weekly paclitaxel. Daily fraction doses of 2.5 Gy and 2.0 Gy were prescribed to the gross tumor volume (GTV) and clinical target volume (CTV) to a total dose of 70 Gy and 56 Gy, respectively. Paclitaxel of 45 mg/m2 was administered concurrently with radiation therapy every week. Adjuvant chemotherapy was given four weeks after the completion of the radiotherapy (RT) if the tumor demonstrated only a partial response (PR). RESULTS: All patients completed the radiotherapy (RT) course. Adjuvant chemotherapy was administered to 12 patients due to PR. The CR (complete remission) rate was 82.9% three months after RT. Thirty-nine (95.1%) patients completed the concurrent weekly chemotherapy with paclitaxel, and two patients skipped their sixth course. Seven patients had a 15% dosage reduction at the fifth and sixth course due to grade 3 mucositis. The median follow-up was 30 (range, 14-42) months. The three-year overall survival (OS), metastases-free survival (MFS), and local control rates were 77.0%, 64.4%, and 97.6%, respectively. No correlation between survival rate and T or N stage was observed. Grade 3 acute mucositis and xerostomia were present in 17.1% and 7.1%, respectively. CONCLUSION: SMART with concurrent weekly paclitaxel is a potentially effective and toxicity tolerable approach in the treatment of locally advanced NPC.

Adjuvant combined systemic chemotherapy and intraperitoneal chemotherapy for locally advanced gastric cancer.

The optimal adjuvant treatment modality for gastric cancer has not been well defined. The aim of this study was to evaluate the efficacy and feasibility of adjuvant combined systemic and intraperitoneal chemotherapy (ACSIP) in high-risk patients with locally advanced gastric cancer. Between June 2003 and December 2008, 62 eligible patients with serosa-infiltrating and/or node-positive gastric cancer following curative gastrectomy with D2 lymphadenectomy received ACSIP, consisting of intravenous oxaliplatin 85 mg/m(2) on day 1 followed by leucovorin (LV) 200 mg/m(2) and 5-fluorouracil (5-FU) 450 mg/m(2) on days 1-3, intraperitoneal 5-FU 600 mg/m(2) on days 4-5 and cisplatin (CDDP) 40 mg/m(2) on day 5. Survival rates, the sites of first treatment failure and safety were analyzed. At a median follow-up of 45 months (range 7-101), the 3-year disease-free survival (DFS) and overall survival (OS) rates were 66.1 and 74.2%, respectively. Initial peritoneal and hepatic failures were found in 6 (24.0%) and 3 (12.0%) of the 25 patients with recurrence, respectively. Neutropenia, gastrointestinal side effects and peripheral neuropathy were the most common grade 3-4 toxicities; however, they were all infrequent and manageable. No serious surgical complications or treatment-related mortality was observed. The results of this study indicate that ACSIP is effective and feasible for locally advanced gastric cancer with encouraging survival rates and possibly decreased peritoneal and hepatic recurrences. The benefits of this promising combined adjuvant treatment modality warrant further studies.

Reverse resistance to radiation in KYSE-150R esophageal carcinoma cell after epidermal growth factor receptor signal pathway inhibition by cetuximab.

BACKGROUND AND PURPOSE: The purpose of our study is to examine the capacity of cetuximab to reverse radiation resistance and investigate molecular mechanisms in human radiation-resistant esophageal carcinoma cell line KYSE-150R. MATERIALS AND METHODS: The radioresistant cell line KYSE-150R was established by using fractionated irradiation (FIR). The KYSE-150R cell line was exposed to radiation, treatment with cetuximab, and combined treatment. Cell cycle distribution and apoptosis were analyzed using flow cytometry. Radiation survival was analyzed using clonogenic assays. RT(2) profiler PCR array was performed to analyze EGF/PDGF signaling pathway genes. RESULTS: The established esophageal carcinoma cell line KYSE-150R showed higher radioresistance than parental cell line. Cetuximab could reverse the radiation resistance of KYSE-150R cells. Cell cycle analysis showed that combination with radiation and cetuximab resulted in the accumulation of cells in G1 and G2/M phases, with the reduction of cells within the S phase. Cetuximab enhanced the apoptosis induced by radiation. RT(2) profiler array showed that some intracellular signaling genes deriving from EGF/PDGF signaling pathway regulated by cetuximab. CONCLUSIONS: Irradiation combined with EGFR blocked by cetuximab may reverse the resistance to radiation in radioresistant esophageal carcinoma cell. The mechanisms may include cell cycle perturbation and enhancement of radiation-induced apoptosis. Further studies are needed to evaluate the role of cetuximab in combination with radiotherapy in the management of esophageal carcinoma.

Analysis of therapeutic result and prognostic factor in primary fallopian tube carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the impact of treatment modality and clinicopathologic profile on prognosis in primary fallopian tube carcinoma.</p><p><b>METHODS</b>The data of 64 cases with primary fallopian tube carcinoma treated between January 1991 and June 2006 were analyzed. The clinicopathological data were retrospectively analyzed.</p><p><b>RESULTS</b>The overall 5-year survival rate of this series was 56.3%. The overall 3- and 5-year survival rate was 84.6% and 65.4% in surgical staging group versus 58.3% and 33.3% in no surgical staging group with a significant difference between two groups (P = 0.0429; P = 0.043), which was 89.5% and 68.4% in optimal cytoreduction group versus 66.7% and 41.7% in suboptimal cytoreduction group (P = 0.0466; P = 0.0444). However, there was no significant difference in 3-year and 5-year survival rate between the group with pelvic lymphadenectomy and the group without (84.2% vs. 69.2%, P = 0.4667; 63.1% vs. 53.8%, P = 0.459), and also between the group treated using CAP/CP regimen and the group by TP regimen for chemotherapy (81.8% vs. 80.0%, P = 0.8946; 59.1% vs. 60.0% P = 0.9582). It was found that the 5-year survival was correlated with FIGO stage (III-IV vs. I - II, P = 0.0197), differentiation grade (G3 vs. G1 + G2, P = 0.003), pathologic type (other type vs. serous, P = 0.0494), lymph nodes status (positive vs. negative, P = 0.0295).</p><p><b>CONCLUSION</b>Surgical staging, optimal cytoreduction, differentiation grade, pathologic type, lymph node status are important factors influencing the 5-year survival in primary fallopian tube carcinoma. Pelvic lymphadenectomy is necessary and feasible to perform during the procedure of surgical staging and cytoreduction. CAP/CP and TP regiment are similarly effective in adjuvant chemotherapy for primary fallopian tube carcinoma.</p>