MicroRNA-101 down-regulates sphingosine kinase 1 in colorectal cancer cells.

MicroRNAs (miRs) dysregulation is a general feature of colorectal cancer (CRC) and other solid tumors, and is associated cancer progression. In the current study, we demonstrate that microRNA-101 (miR-101) inhibits CRC cells probably through down-regulating sphingosine kinase 1 (SphK1). Our results showed that exogenously expressing miR-101 inhibited CRC cell (HT-29 and HCT-116 lines) growth in vitro. At the molecular level, miR-101 dramatically down-regulated SphK1 mRNA and protein expression, causing pro-apoptotic ceramide production in above CRC cells. On the other hand, inhibition of miR-101 through expressing antagomiR-101 increased SphK1 expression to down-regulate ceramide level in HT-29 cells. miR-101 expression increased the in vitro anti-CRC activity of conventional chemo-agents: paclitaxel and doxorubicin. CRC cells with SphK1-shRNA knockdown showed similar phenotypes as the miR-101-expressed CRC cells, presenting with elevated level of ceramide and high sensitivity to paclitaxel or doxorubicin. In vivo, HCT-116 xenograft growth in severe combined immuno-deficient (SCID) mice was dramatically inhibited by over-expressing miR-101. Further, miR-101 enhanced paclitaxel-induced anti-HCT-116 activity in vivo. Together, these results indicate that miR-101 exerts its anti-CRC activities probably through down-regulating SphK1.

Copy number variation at 6q13 is associated with lung cancer risk in a Han Chinese population.

Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases, and neurological disorders. Lung cancer is a multifactorial tumor closely associated with genetic background. Previous genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with lung cancer susceptibility. This study examined the CNVR2966.1 at 6q13 and its association with lung cancer susceptibility. The CNVR2966.1 was found to be a 10,379 bp nucleotides deletion/insertion within the uniform boundaries chromosome 6: 74,648,791-74,659,169. The risk of lung cancer observed in 503 cases and 623 controls was significantly associated with copy number of CNVR2966.1, with the odds ratio (OR) being 1.38 [95% confidence interval (CI) = 1.05-1.79; P = .007] for one copy genotype compared with two copies genotype. These results suggest that CNVR2966.1 is associated with lung cancer risk.

Comparison of radiotherapeutic management of operated breast cancer in 1999 and in 2006: a sampling survey on the southeast coast of China.

AIMS: To obtain a better understanding of the changes in radiotherapeutic management of breast cancer patients in the more developed areas of China over the past decade. METHODS: Four academic radiation therapy departments located on the Southeast Coast of China were selected for the study. The survey was conducted on female breast cancer patients who received radiotherapy in 1999 and 2006. The questionnaires were designed to determine the purposes of radiotherapy and to address the postoperative radiotherapy techniques used. The data for these two years were analyzed and compared. RESULTS: The percentage of breast-conserving treatment increased from 3% in 1999 to 13% in 2006, but the percentage of patients treated with postmastectomy radiotherapy dropped from 69% in 1999 to 66% in 2006 (P < 0.05). As regards the changes in techniques from 1999 to 2006, the use of special immobilization devices, treatment planning systems, and CT simulations increased from 46% to 80%, 23% to 70%, and 0% to 14%, respectively (P <0.01). From 1999 to 2006, irradiation of the chest wall following mastectomy increased from 67% to 90%, but for internal mammary irradiation it decreased from 76% to 30% and for the axilla, from 69% to 37% (P < 0.01). There were no obvious differences between 1999 and 2006 on the field design, boost treatment on the tumor bed, or dose prescription. CONCLUSIONS: Breast-conserving treatment was performed more frequently in China in 2006 than in 1999, but postmastectomy radiotherapy did not change a great deal and it was still an essential option. Although the international treatment guidelines have been accepted and implemented by physicians in recent years, prompt improvement in the quality of breast cancer radiotherapy is needed.

The incidence and risk factors of related lymphedema for breast cancer survivors post-operation: a 2-year follow-up prospective cohort study.

PURPOSE: To investigate the incidence rate, severity and risk factors of related lymphedema in breast cancer survivors. METHODS: A 2-year follow-up prospective study of 387 women who had operation from four hospitals from January 1, to December 31, 2014 was conducted. Limb volume was measured by circumference and symptoms were measured using questionnaires pre-treatment and 1, 3, 6, 12, 18, 24 months after surgery separately. The incidence rates and the severity of lymphedema were evaluated, respectively. Risk factors for the development of breast cancer-related lymphedema (BCRL) were analyzed using log-rank test and Cox regression. RESULTS: The incidences of BCRL were 4.4, 10.1, 15.2, 28.6, 31.2 and 32.5% at 1, 3, 6, 12, 18, 24 months after surgery, respectively, measured by Norman questionnaire. The rates measured by arm circumference were 2.5, 6.7, 13.4, 21.4, 26.3 and 29.4%, respectively. About 114 (29.4% of 387) women were diagnosed with BCRL, and 78 of them got mild lymphedema. Axillary lymph node dissection (ALND) (HR = 5.2, 95% CI 1.6-17.3), radiotherapy (HR = 3.9, 95% CI 2.0-7.5), modified radical mastectomy (MRM) (HR = 2.1, 95% CI 1.3-3.4), the number of positive lymph nodes (HR = 1.1, 95% CI 1.0-1.2) and body mass index (BMI) (HR = 1.1, 95% CI 1.0-1.1) were independent risk factors for BCRL. CONCLUSIONS: BCRL is a common complication for breast cancer patients after surgery. It can be fairly diagnosed only 1 month post-operation and the cumulative incidence of BCRL seems to be increasing over time, especially in the first year after surgery. ALND, radiotherapy, MRM, the number of positive axillary lymph nodes and BMI were found to be independent risk factors in the development of BCRL in this study.

Prognostic value of increased KPNA2 expression in some solid tumors: A systematic review and meta-analysis.

BACKGROUND: Karyopherin α2 (KPNA2), a member of the Karyopherin α family, has recently been reported to play an important role in tumor progression. However, the association between KPNA2 expression and prognosis in cancer remains controversial. So we performed this meta-analysis to evaluate whether expression of KPNA2 was associated with prognosis in patients with solid tumor. METHODS/FINDINGS: 24 published eligible studies, including 6164 cases, were identified and included in this meta-analysis through searching of PubMed, EMBASE and Web of Science. We found that KPNA2 expression was an independent predictor for the prognosis of solid tumor with primary outcome (overall survival [OS]: pooled HR=1.767, 95% CI=1.503-2.077, P<0.001) and secondary outcomes (time to recurrence [TTR], recurrence free survival [RFS] and progression free survival [PFS]). However, the association between KPNA2 overexpression and disease free survival [DFS] in solid tumors was not significant (pooled HR=1.653, 95% CI=0.903-3.029, P=0.104). Furthermore, the subgroup analysis revealed that KPNA2 overexpression was associated with poor OS in East-Asian patients and European patients, as well as patients with gastric and colorectal cancer. CONCLUSION: KPNA2 expression may be a useful prognostic biomarker to monitor cancer prognosis. Further prospective studies with larger sample sizes are required to confirm our findings.

TMPRSS4 as an emerging potential poor prognostic factor for solid tumors: A systematic review and meta-analysis.

Recent studies have investigated the potential prognostic value of the transmembrane protease serine 4 (TMPRSS4) in various solid tumors. Yet, the results are inconclusive. Here, we performed this meta-analysis to clarify this issue. Relevant articles were identified by searching PubMed, Web of Science and Embase databases. The primary outcome endpoints were patients' overall survival (OS) and time to tumor progression (TTP). Twelve studies involving 1,955 participants were included. We showed that high TMPRSS4 expression in tumor tissues was significantly associated with patients' poor OS (pooled HR = 2.981, 95% CI = 2.296-3.869, P < 0.001) and short TTP (pooled HR = 2.456, 95% CI = 1.744-3.458, P < 0.001). A subgroup analysis revealed that the association between TMPRSS4 and the outcome endpoints (OS or TTP) was also significant within China region. We conclude that TMPRSS4 overexpression in solid tumors is associated with patients' poor prognosis. TMPRSS4 could be a valuable prognosis biomarker or a promising therapeutic target of solid tumor.

Ionizing irradiation inhibits keloid fibroblast cell proliferation and induces premature cellular senescence.

Keloids are one of the common refractory conditions in dermatology and aesthetic plastic surgery. The most effective treatment is superficial radiotherapy followed by surgical removal. The rate of recurrence is strongly associated with the total dose of ionizing irradiation, and the underlying mechanism remains unclear. In this study, we used primary keloid fibroblasts (KFb) isolated from patient samples to investigate the effects of X-ray radiation on cell proliferation, cell toxicity and cell cycle, as detected by CCK-8 assay kit and flow cytometer. In addition, we examined senescence-associated ß-galactosidase activity and the associated gene expression using real-time polymerase chain reaction and western blot in KFb exposed to X-ray radiation. X-ray radiation inhibited cell proliferation and induced cell senescence in KFb in a dose-dependent manner. Inhibition of cell proliferation and induction of cellular senescence were mediated by interruption of the cell cycle with an extended G0/G1 phase. Furthermore, the expressions of senescence-associated genes p21, p16 and p27 were upregulated both at mRNA and protein levels in KFb exposed to X-ray radiation. Taken together, our data indicate that X-ray radiation may prevent the recurrence of keloids by controlling fibroblast proliferation, arresting the cell cycle and inducing premature cellular senescence.

Systemic analysis on risk factors for breast cancer related lymphedema.

BACKGROUND: To evaluate risk factors for upper extremity lymphedema due to breast cancer surgery. MATERIALS AND METHODS: Clinical studies published on PubMed, Ovid, EMbase, and Cochrane Library from January 1996 to December 2012 were selected. RESULTS: Twenty-five studies were identified, including 12,104 patients. Six risk factors related to the incidence of lymphedema after breast cancer treatment were detected: axillary lymph node dissection (OR=3.73, 95%CI 1.16 to 11.96), postoperative complications (OR=2.64, 95%CI 1.10 to 6.30), hypertension (OR=1.83, 95%CI 1.38 to 2.42), high body mass index (OR=1.80, 95%CI 1.30 to 2.49), chemotherapy (OR=1.38, 95%CI 1.07 to 1.79) and radiotherapy (OR=1.35, 95%CI 1.10 to 1.66). We found significant protective factors for lymphedema: pathologic T classification (OR=0.57, 95%CI 0.36 to 0.91) and stage (OR=0.60, 95%CI 0.39 to 0.93), while some factors, like age, number of positive lymph nodes, number of lymph node dissection, demonstrated no obvious correlation. CONCLUSIONS: Axillary lymph node dissection, postoperative complications, hypertension, body mass index, chemotherapy, radiotherapy are risk factors for lymphedema after breast cancer treatment. Attention should be paid to patients with risk factors to prevent the occurrence of lymphedema.

Doxorubicin induces drug resistance and expression of the novel CD44st via NF-κB in human breast cancer MCF-7 cells.

CD44, a major receptor for hyaluronan (HA), is a member of a class of adhesion molecules of unknown classification involved in cell proliferation, differentiation, migration, angiogenesis, and the presentation of specific cytokines to the corresponding receptors as well as in cell signaling transduction. It has recently been discovered that CD44, a marker of tumor stem cells, is involved in the drug resistance and invasion of multiple types of tumors. The 20 exons in the CD44 gene that are alternatively spliced, give rise to many CD44 isoforms, possibly including tumor-specific sequences. Dozens of CD44 isoforms have been found, to date, and the standard CD44 (CD44s) isoform is the most common. We recently showed that a novel short-tail isoform of CD44 (CD44st) was expressed in multidrug-resistant human breast cancer MCF-7/Adr cells. Moreover, the novel CD44st was able to interact with HA and regulate the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which increased the invasive capability of MCF-7 cells through the Ras/MAPK signaling pathway. In the present study, we verified that MCF-7 cells subjected to drug pressure develop multidrug resistance to doxorubicin, and the expression levels of multidrug resistance protein 1 (MDR1), CD44st and nuclear factor-κB (NF-κB) mRNA and protein were gradually upregulated in a dose­dependent manner in MCF-7 cells treated with doxorubicin. HA increases the secretion of MMP-2 and MMP-9 in multidrug-resistant MCF-7 cells and affected the invasive ability of MCF-7 cells through the upregulation of CD44st expression, and such an effect was blocked by the NF-κB-specific inhibitor BMS-345541.

Value of TP53 status for predicting response to neoadjuvant chemotherapy in breast cancer: a meta-analysis.

BACKGROUND: Numerous studies have yielded inconclusive results regarding the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to neoadjuvant chemotherapy in patients with breast cancer. The purpose of the current study was therefore to evaluate the relationship between TP53 status and response to chemotherapy in breast cancer. METHODS AND FINDINGS: A total of 26 previously published eligible studies including 3,476 cases were identified and included in this meta-analysis. TP53 status (over expression of TP53 protein and/or TP53 gene mutations) was associated with good response in breast cancer patients who received neoadjuvant chemotherapy (total objective response: risk ratio [RR]= 1.20, 95% confidence interval [CI]= 1.09-1.33, p<0.001; pathological objective response: RR = 1.37, 95% CI = 1.20-1.57, p<0.01; total complete response: RR = 1.33, 95% CI = 1.15-1.53, p<0.001; pathological complete response: RR = 1.45, 95% CI = 1.25-1.68, p<0.001). In further stratified analyses, this association also existed among the studies using anthracycline-based neoadjuvant chemotherapy, and the association between response and the presence of gene alterations was stronger than that between response and immunohistochemistry positivity. CONCLUSION: The results of the present meta-analysis suggest that TP53 status is a predictive factor for response in breast cancer patients undergoing neoadjuvant chemotherapy. Further larger and well-designed prospective studies are required to evaluate the predictive role of TP53 status in clinical practice.