Nm23 Expression Research Articles

TIF1γ and SMAD4 regulation in colorectal cancer: impact on cell proliferation and liver metastasis.

We investigated the effects of transcriptional intermediary factor 1γ (TIF1γ) and SMAD4 on the proliferation and liver metastasis of colorectal cancer (CRC) cells through knockdown of TIF1γ and/or SMAD4 and knockdown of TIF1γ and/or restoration of SMAD4 expression. Furthermore, we examined TIF1γ and SMAD4 expression in human primary CRC and corresponding liver metastatic CRC specimens. TIF1γ promoted but SMAD4 inhibited the proliferation of CRC cells by competitively binding to activated SMAD2/SMAD3 complexes and then reversely regulating c-Myc, p21, p27, and cyclinA2 levels. Surprisingly, both TIF1γ and SMAD4 reduced the liver metastasis of all studied CRC cell lines via inhibition of MEK/ERK pathway-mediated COX-2, Nm23, uPA, and MMP9 expression. In patients with advanced CRC, reduced TIF1γ or SMAD4 expression was correlated with increased invasion and liver metastasis and was a significant, independent risk factor for recurrence and survival after radical resection. Patients with advanced CRC with reduced TIF1γ or SAMD4 expression had higher recurrence rates and shorter overall survival. TIF1γ and SMAD4 competitively exert contrasting effects on cell proliferation but act complementarily to suppress the liver metastasis of CRC via MEK/ERK pathway inhibition. Thus, reduced TIF1γ or SMAD4 expression in advanced CRC predicts earlier liver metastasis and poor prognosis.

Combined dandelion extract and all-trans retinoic acid induces cytotoxicity in human breast cancer cells

Breast cancer is one of the most prevalent and deadly cancers among women worldwide. Recently, natural compounds have been widely used for the treatment of breast cancer. Present study evaluated antiproliferative and anti-metastasis activities of two natural compounds of dandelion and all-trans-retinoic acid (ATRA) in human MCF-7 and MDA-MB231 breast cancer cells. We also evaluated the expression of MMP-2, MMP-9, IL-1β, p53, NM23 and KAI1 genes. Data showed a clear additive cytotoxic effect in concentrations of 40 μM ATRA with 1.5 and 4 mg/ml of dandelion extract in MCF-7 and MDA-MB231 cells, respectively. In both cell lines, compared with the untreated cells, the expression levels of MMP-9 and IL-1β were significantly decreased while p53 and KAI1 expression levels were increased. Besides, MMP-2 and NM23 had different expressions in the two studied cell lines. In conclusion, dandelion/ATRA co-treatment, in addition to having strong cytotoxic effects, has putative effects on the expression of anti-metastatic genes in both breast cancer cells.

Diagnostic significance of NM23 protein in ameloblastoma and ameloblastic carcinoma: An immunohistochemical study

BackgroundClinico-histopathologic assessment of patients with ameloblastoma and ameloblastic carcinoma remains the best diagnostic modality for the tumors. However, in cases where the criteria for arriving at a definitive diagnosis are not clearcut, the pathologist is faced with a dilemma and thus an imperative need for adjunct diagnostic methods. ObjectivesTo evaluate/compare the immunohistochemical expression of NM23 in classical, borderline (atypical) ameloblastoma and ameloblastic carcinoma and to assess usefulness of NM23 in closing diagnostic gaps between ameloblastoma and ameloblastic carcinoma. MethodsTwenty-four (24) cases of ameloblastoma, 10 ameloblastoma with classical histopathologic features, 8 with nonclassical histopathology [atypical], and 6 cases of ameloblastic carcinoma were selected from cases seen at the Oral Pathology Laboratory of the Lagos State University College of Medicine, Nigeria. NM23 immunostaining protocol was done on the selected tissue blocks and evaluated using Sinicrope method. Analysis was done using R language. ResultsPositive NM23 staining was observed in all cases of ameloblastoma and ameloblastic carcinoma, with more intense staining observed in the stellate reticulum-like areas than in the ameloblast-like areas. Ameloblastic carcinoma stained intensely with NM23 (100%) compared with atypical cases (37.5%) and ameloblastoma (20.0%; p = 0.04). The mean aggregate score was also significantly higher in AC (11 ± 2.4; p = 0.01). The mean aggregate score was also significant amongst growth pattern of ameloblastoma (p = 0 0.02). ConclusionsThe findings in this study reveal the usefulness of NM23 in differentiating ameloblastoma from ameloblastic carcinoma; a more comprehensive study with a larger sample size is recommended to corroborate or refute the findings in this study.

Aberrant expression of SPAG6 and NM23 predicts poor prognosis of human osteosarcoma.

Objective: To investigate the expression and clinical significance of sperm-associated antigen 6 and NM23 proteins in human osteosarcoma. Methods: The specimens of conventional osteosarcoma with follow-up from 42 Chinese patients were analyzed in this study, and 12 cases of osteochondroma were considered controls. The expression of SPAG6 and NM23 was inspected using immunohistochemical staining, qRT-PCR, and Western blotting methods. Results: The positive expression rate of SPAG6 protein (71.43%) in 42 cases of osteosarcoma tissue was significantly higher than that (33.33%) in 12 cases of osteochondroma tissues (p < 0.05), while the positive rate of NM23 protein (35.71%) in osteosarcoma tissue was lower than that (58.33%) in osteochondroma tissue (p < 0.05). The mRNA and protein levels of SPAG6 were significantly higher than those of the adjacent normal tissues, while the expression of NM23 was lower in osteosarcoma tissues than that in the controls (p < 0.05 for all). There was a positive relationship between the expression of SPAG6 and pathological grade, metastasis, and Enneking stage (p < 0.05 for all). The overall survival rate of osteosarcoma patients with SPAG6 positive expression was significantly lower than that with SPAG6 negative expression. The relationship between the expression of NM23 and pathological grade, metastasis, and Enneking stage was negative (p < 0.05 for all). The overall survival rate of the osteosarcoma patients with NM23 positive expression was higher than that of the patients with NM23 negative expression (p < 0.05). Conclusion: Overexpression of SPAG6 and low expression of NM23 are negatively related to pathological grade, metastasis, and Enneking stage and prognosis of osteosarcoma patients. This suggested that SPAG6 and NM23 should be considered candidate prognostic biomarkers for patients with osteosarcoma.

High-Expression of Cytoplasmic Poly (A) Binding Protein 1 (PABPC1) as a Prognostic Biomarker for Early-Stage Esophageal Squamous Cell Carcinoma

Background and ObjectivePoly (A) binding protein cytoplasmic 1 (PABPC1) plays a crucial role in the regulation of RNA polyadenylation, translation initiation, and mRNA stability and may be involved in tumorigenesis. Herein, we set out to identify the prognostic value of PABPC1 expression in esophageal squamous cell carcinoma (ESCC).MethodsUsing quantitative real-time PCR (qRT-PCR) and immunohistochemical analysis, the present study investigated mRNA and protein expressions of PABPC1 in 231 ESCCs and their paired adjacent normal epithelial tissues.ResultsWe observed a reduction in the average mRNA expression of PABPC1 in ESCC tissue specimen, but the mRNA expression of PABPC1 was significantly higher (P<0.001) in ESCC tissues with high PABPC1 expression and lower (P=0.033) in tissues with low PABPC1 expression. In immunohistochemical analysis, positive expression of the PABPC1 protein was identified in 179 ESCC tissue specimens (179/231, 77.5%), while the percentage of ESCC tissue specimens with high expression of PABPC1 was found to be 41.1% (95/231). PABPC1 expression was found to be significantly correlated with lymph node metastasis (LNM) (P=0.011), pathological stage (P=0.021), tumor recurrence (P<0.001), and the outcome (P<0.001) of patients with ESCC. High expression of PABPC1 was associated with poor overall survival (OS) of ESCC patients (P<0.001) among all pathological stages, particularly in the early stages (pStage-I and -II), and identified to be an independent prognostic factor for OS of patients with ESCC in multivariate analysis (HR=2.622; 95% CI, 1.68–4.129). Comparatively, the expression of Ki-67, p53, and nm23 was not associated with OS.ConclusionIn this study, we discovered that PABPC1 is a prognostic biomarker and a therapeutic target for ESCC, particularly early-stage ESCC.

IMMUNOHISTOCHEMICAL EXPRESSION AND DIAGNOSTIC SIGNIFICANCE OF NM23 PROTEIN IN AMELOBLASTOMA AND AMELOBLASTIC CARCINOMA

<h3>Background</h3> Clinicohistopathologic assessment of patients with ameloblastoma and ameloblastic carcinoma remains the best diagnostic modality for the tumors. However, in cases where the criteria for arriving at a definitive diagnosis are not clearcut, the pathologist is faced with a dilemma and thus an imperative need for adjunct diagnostic methods. <h3>Objectives</h3> 1. To evaluate/compare the immunohistochemical expression of NM23 in classical, borderline (atypical) ameloblastoma and ameloblastic carcinoma. 2. To assess usefulness of NM23 in closing diagnostic gaps between ameloblastoma and ameloblastic carcinoma. <h3>Methods</h3> Twenty-four cases of ameloblastoma (10 ameloblastoma with classical histopathologic features, 8 with nonclassical histopathology [atypical], and 6 cases of ameloblastic carcinoma) were selected from cases seen at the Oral Pathology Laboratory of the Lagos State University College of Medicine, Lagos, Nigeria. NM23 immunostaining protocol was done on the selected tissue blocks and evaluated using the Sinicrope method. Analysis was done using STATA 14. <h3>Results</h3> Positive NM23 staining was observed in all cases of ameloblastoma and ameloblastic carcinoma, with more intense staining observed in the stellate reticulum-like areas than in the ameloblast-like areas. Ameloblastic carcinoma stained intensely with NM23 (100%) compared with atypical cases (37.5%) and ameloblastoma (20.0%; <i>P</i> = .04). The mean aggregate score was also significantly higher in AC (11 ± 2.4; <i>P</i> = .01). The mean aggregate score was also significant amongst growth pattern of ameloblastoma (<i>P</i> = .02). <h3>Conclusions</h3> The findings in this study reveal the usefulness of NM23 in differentiating ameloblastoma from ameloblastic carcinoma; a more comprehensive study with a larger sample size is recommended to corroborate or refute the findings in this study.

LINC00636 promotes lymph node metastasis and cervical cancer through targeting NM23.

Background: Metastasis is a major obstacle in treatment of cervical cancer, and long non-coding RNA (lncRNA) mediated regulatory effect on associated genes expression is found to be involved in metastasis. However, its mechanisms have not been fully elucidated.Materials and methods: Specimens from patients with cervical cancer metastasis and non-metastasis were used to screen out candidate non-coding RNAs (ncRNAs) and possible downstream targets. And then, effects were determined in vitro and in vivo through knockdown and overexpression techniques.Results: LINC00636 was significantly higher in serum and solid tumor cells of metastatic cervical cancer patients than non-metastatic patients. And knockdown of LINC00636 significantly suppressed invasion, proliferation of cervical cancer cells. NM23 expression was negatively regulated by LINC00636 and it mediated anti-tumor effects was partially blocked by overexpression of LINC00636.Conclusion: LINC00636 might promote metastasis of cervical cancer cells through inhibiting NM23 expression.

Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy.

Objective: The goal of our current study is to assess the immunohistochemical of p53, p21, nm23, and VEGF expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) prognosis after hepatectomy, as well as the prospective molecular mechanisms of prognostic indicator.Methods: There were 419 HBV-related HCC patients who were from southern China of Guangxi province and were used to evaluate the immunohistochemical expression for these biomarkers in prognosis. A genome-wide expression microarray dataset of HBV-related HCC were obtained from GSE14520.Results: In our study, the expression of p53, p21, and nm23 in cancer tissues of patients with hepatitis B-related hepatocellular carcinoma did not affected the clinical outcome of 2 years, 5 years or overall. Patients with high expression of VEGF had a worse overall survival after 2 years of surgery than patients with low expression (adjusted P=0.040, adjusted HR = 1.652, 95% CI = 1.024-2.665). Survival analysis of VEGF in GSE14520 cohort also demonstrated that VEGF mRNA expression also significantly associated with HBV-related HCC OS (adjusted P=0.035, adjusted HR =1.651, 95% CI =1.035-2.634). The prospective molecular mechanisms by co-expression analysis suggested that VEGF might be correlated to regulation of cell proliferation, cell growth and apoptotic process, Rap1 signaling pathway, HIF-1 signaling pathway, PPAR signaling pathway, cell cycle. Whereas the GSEA suggested that VEGF might involve in the regulation of HIF and HIF1A pathway, and TP53 regulation pathway.Conclusion: Our findings suggested that VEGF might be a prognostic indicator of HBV-related HCC, and we also identified the VEGF prospective molecular mechanisms through the whole genome co-expression and GSEA approaches.

Nm23, TOP2A and VEGF expression: Potential prognostic biologic factors in peripheral T-cell lymphoma, not otherwise specified.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is an aggressive lymphoma associated with a poor outcome. To date, the factor consistently associated with prognosis is the International Prognostic Index (IPI) score; however, it is considered that the IPI score cannot be beneficial for guiding potential targeted therapies. New scoring systems have recently been developed. The aim of the present study was to observe the expression of NME/NM23 nucleoside diphosphate kinase 1 (nm23), nuclear DNA topoisomerase 2-α (TOP2A), multiple myeloma oncogene-1 (MUM-1) and vascular endothelial growth factor (VEGF), and evaluate their prognostic value in PTCL-NOS. A retrospective analysis of 124 cases of PTCL-NOS showed that 70/122 (57.4%) cases were positive for nm23, 71/122 (58.2%) for TOP2A, 30/119 (25.2%) for MUM-1 and 64/122 (52.5%) for VEGF. Of note, 50/122 cases concurrently expressed nm23, TOP2A and VEGF. The univariate analysis results revealed that the nm23 (P=0.012), TOP2A (P=0.002) and VEGF (P=0.008) expression had a negative prognostic effect in patients with PTCL-NOS, while the MUM-1 expression did not have a significant prognostic value (P=0.918). In addition, the concurrent expression of nm23, TOP2A and VEGF was significantly associated with a worse prognosis (P=0.002). However, in multivariate Cox regression analysis, the concurrent expression of nm23, TOP2A and VEGF tended to predict a worse prognosis, however the P-value was borderline (hazard ratio, 1.495; 95% confidence interval, 0.993-2.250; P=0.054). It is speculated that there may be an association among the expression of nm23, TOP2A and VEGF, and that their expression may serve as a promising prognostic factor for PTCL-NOS.

Prognostic significance of metastasis-suppressor gene NM23 in gastric carcinoma

Aim: Metastasis is critical in the prognosis of gastric cancer patients and in deciding on treatment strategies. Therefore, studies have concentrated on metastasis suppressor genes. This study aimed to identify the characteristics of NM23 expression in gastric cancer and to investigate its anti-metastatic and prognostic significance.Methods: Ninety patients who underwent surgery for gastric cancer between January 1, 2009 and January 1, 2010 were included in this study. Immunohistochemical staining was applied to specimen sections. The results of the immunohistochemical staining were evaluated with the normal gastric mucosa adjacent to the tumor. The degree of NM23 staining of tumor cell compared to the normal tissue was evaluated in two groups of “negative-weak staining” and “strong staining”. Both groups were analyzed for lymph node metastasis, vascular invasion, perineural invasion, degree of tumor differentiation, tumor stage and distant metastasis.Results: Among 58 patients with lymph node metastasis, 70.7% showed negative-weak staining and 29.3% showed strong staining. Among 32 patients with no lymph node metastasis, 40.6% had negative-weak staining and 59.4% had strong staining. Decrease in NM23 expression was shown to cause an increase in lymph node metastasis (P=0.01). Furthermore, while there was no statistical significance, the rates of distant metastasis, degree of poor differentiation, tumors in stage III and stage IV were apparently higher in the negative-weak staining group. These results were in line with the anti-metastatic property of NM23. Conclusion: This study showed that NM23 expression had anti-metastatic properties for lymph node metastasis in gastric cancer patients.

Taxol Inhibits Melanoma Metastases Through Apoptosis Induction, Angiogenesis Inhibition, and Restoration of E-Cadherin and nm23 Expression

Taxol Inhibits Melanoma Metastases Through Apoptosis Induction, Angiogenesis Inhibition, and Restoration of E-Cadherin and nm23 Expression

Clinical Implication and the Hereditary Factors of NM23 in Hepatocellular Carcinoma Based on Bioinformatics Analysis and Genome–Wide Association Study

NM23 expression is closely associated with hepatocellular carcinoma (HCC) recurrence, but the hereditary factors influencing NM23 levels are unknown. Using public database, the diagnostic value of NM23 in HCC was investigated. A total of 424 hepatitis B virus- (HBV-) related HCC patients were enrolled to perform a genome–wide association study for identifying candidate variants associated with NM23 expression level. Additionally, a logistic regression model, haplotypes, and survival analysis were performed in the subsequent analysis. We identified high NM23 expression levels that have a diagnostic accuracy in HCC tissues and had a poor recurrence-free survival in HBV-related HCC patients. Variants near Psoriasis susceptibility 1 candidate 1 (PSORS1C1) and StAR related lipid transdomain containing 3 (STARD3) are associated with NM23 expression. The PSORS1C1 haplotype TGCACA and the STARD3 haplotype GG have favorable cumulative effects on NM23 expression. Further, variants in PSORS1C1 were associated with either overall survival (rs556285588, rs3095301, and rs3131003) only or overall survival and recurrence-free survival (rs560052000 and rs541820233) both in HCC patients. Our findings suggested that variants at the PSORS1C1 and STARD3 loci play an important role in NM23 regulation. Moreover, variants in PSORS1C1 are potential biomarkers for the prediction of postoperative clinical outcomes in HBV-related HCC patients. Thus, variants in PSORS1C1 and STARD3 are associated with NM23 expression and clinical outcomes of HBV-related HCC patients, which may be regarded as potential biomarkers for this disease.

Correlation of SOX9 and NM23 genes with the incidence and prognosis of prostate cancer.

Correlation of sex determining region Y-box (SOX)9 and NM23 genes with the incidence and prognosis of prostate cancer (PC) was investigated. SOX9-small interfering ribonucleic acid (siRNA) and NM23-siRNA were constructed and transfected into PC-3 cells. The expression levels of SOX9 and NM23 messenger RNAs (mRNAs) and proteins in PC-3 cells were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. MTT assay was adopted to examine the proliferation ability of the transfected cells, and Transwell assay was applied to detect the migration ability of the transfected cells. Sixty-three patients with PC and 56 patients with benign prostatic hyperplasia who were treated in Huadu District People's Hospital were enrolled. Correlation analyses were conducted for the relative expression levels of SOX9 and NM23 and the Gleason grade; and the survival curves of the patient SOX9/NM23 (S/N) Cq values were plotted. The proliferation and migration abilities of PC-3 cells were remarkably reduced after low expression of SOX9 (P<0.01), while those of PC-3 cells were significantly improved after low expression of NM23 (P<0.01). Compared with that in tissues of PC patients, the relative expression of SOX9 mRNA in patients with benign prostatic hyperplasia was obviously decreased (P<0.01), while that of NM23 mRNA was significantly elevated (P<0.01). The larger the S/N was, the shorter the patient's survival time would be (P<0.05). The low expression of SOX9 gene can significantly reduce the proliferation and migration abilities of PC cells, which is negatively associated with the incidence and prognosis of patients. The low expression of NM23 gene can markedly enhance the proliferation and migration abilities of PC cells, and it is positively related to the incidence and prognosis of patients.

Inhibition effects of Yuxiao San combined with cisplatin on transplanted tumor growths via upregulation of nm-23 and downregulation of K-ras in Lewis lung cancer mice.

Traditional Chinese medicine applied to cancer therapy has a long history. This study aimed to investigate the effect and underlying mechanism of the traditional Chinese medicine, Yuxiao San, in combination with cisplatin, on Lewis lung cancer mice. Lewis lung cancer mouse models were were established in mice, and were randomly divided into model (normal saline + egg white), cisplatin (cisplatin injection + egg white), traditional Chinese medicine (Yuxiao San + egg white) and combined medication (Yuxiao San + cisplatin injection + egg white) groups. The weight and tumor size of mice was measured every 3 days, and the number of lung surface metastasis nodules were calculated after 14 days. Nucleoside diphosphate kinase (nm-23) and K-ras expression levels in tumor tissues were determined by immunohistochemical methods and reverse transcription- quantitative polymerase chain reaction. The results suggested that compared with the model group, cisplatin, traditional Chinese medicine and combined medication groups significantly inhibited growth of transplanted tumors, reduced the number of lung metastasis nodules, increased the inhibition rate of lung metastasis (P<0.05 or P<0.01), significantly increased tumor suppressor gene nm-23 expression and significantly downregulated oncogene K-ras expression. Among all groups, the effect of the combined medication group for inhibiting tumor growth was most favorable (P<0.01). Compared with the cisplatin group, nm-23 expression in the traditional Chinese medicine group and the combined medication group was significantly increased, and K-ras expression in the traditional Chinese medicine and combined medication groups was significantly reduced (P<0.01). To conclude, Yuxiao San and cisplatin injection effectively inhibited growth of the transplanted tumor. The underlying mechanism may be associate with nm-23 upregulation and K-ras downregulation. Therefore, the Yuxiao San and cisplatin injection may become a potential therapeutic strategy for tumor treatment.

Expression of metastasis associated genes nm23, p53 and S100A4 in conjunctival melanoma and their relationship with invasion and metastasis

Objective To study the significance of metastasis associated genes nm23, p53 and S100A4 in the development of conjunctival melanoma metastasis. Methods Conjunctival melanoma tissue specimens were collected from 42 cases of conjunctival melanoma patients in Henan Eye Hospital from July 2015 to November 2016, meanwhile 30 cases of conjunctival nevus tissue samples served as control group under the informed consent.The expressions of nm23, p53 and S100A4 were detected in conjunctival melanoma group and control group by Western blot and immunohistochemical method.The relationship between the clinical and pathological features of nm23, p53 and S100A4 with conjunctival melanoma patients with lymph nodes metastasis were analyzed. Results Western blot assay showed that the expression level of nm23 in conjunctival melanoma group was lower than that in the control group , with a significant difference between them (P 0.05). There were siginificant differences in nm23, p53 and S100A4 protein expression positive rate between various sclera invasion groups and various distant metastasis groups (all at P<0.05). Conclusions Expression of nm23, p53 and S100A4 may play an important role in the invasion and metastasis of conjunctival melanoma, which may be the main reference index for the diagnosis and treatment. Key words: Conjunctival melanoma; nm23; p53; S100A4; Invasion; Metastasis

NM23 downregulation and lysophosphatidic acid receptor EDG2/lpa1 upregulation during myeloid differentiation of human leukemia cells

The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels.

Prognostic value of NM23 in patients with gastric cancer: A systematic review and meta-analysis.

NM23, as a possible biomarker of prognosis in malignant tumors, has generated remarkable interest in this critical period of the high morbidity and mortality of malignancies. Thus, we launched this meta-analysis to investigate the predictive value of NM23 expression in patients with gastric cancer. We searched PubMed, Embase, and Web of Science for relevant articles. The pooled odds ratios (ORs) and corresponding 95% confidence interval (CI) were calculated to evaluate the prognostic value of NM23 expression in patients with gastric cancer and the association between NM23 expression and clinicopathological factors. We also performed subgroup analyses to find the source of heterogeneity. Exactly, 2674 patients were pooled from 19 available studies in total. The incorporative OR combined by 11 studies with overall survival (OS) showed no significance (OR = 0.90, 95% CI: 0.51-1.58, P = 0.71). Although we failed to find any significance in N status and tumor node metastasis (TNM) staging (P = 0.23 and P = 0.74, respectively), elevated NM23 expression was related to well tumor differentiation (OR = 0.62, 95% CI: 0.41-0.95, P = 0.03). However, in the subgroup analyses, we could not find any potential source of heterogeneity. The results showed that statistically significant association was found between NM23 expression and the tumor differentiation of patients with gastric cancer, but no significance was found in OS, N status, and TNM staging. More and further researches should be conducted to reveal the prognostic value of NM23.

Roles of KAI1 and nm23 in lymphangiogenesis and lymph metastasis of laryngeal squamous cell carcinoma

BackgroundLymphatic metastasis contributes to the poor prognosis of laryngeal squamous cell carcinoma (LSCC). This study aimed to investigate the roles of two metastasis suppressor genes, KAI1 and nm23, in lymphangiogenesis and lymph metastasis of LSCC.MethodsA total of 45 LSCC patients were enrolled in this study. The positive expression rates of KAI1 and nm23 protein were detected via immunohistochemistry in 45 LSCC and 22 normal laryngeal mucosa adjacent to LSCC. Micro-lymphatic vessel density (MLVD) was detected via immunohistochemistry with the specific antibody D2-40. Associations between KAI1 and nm23 expression and clinical characteristics of LSCC were then evaluated.ResultsThe positive expression rates of KAI1 and nm23 were significantly lower in LSCC than normal laryngeal mucosa (P < 0.05). Significantly lower positive rates of KAI1 and nm23 were found in LSCC with lymphatic metastasis than those without lymphatic metastasis (P < 0.05), whereas MLVD was negatively correlated with the expression of KAI1 and nm23 (P < 0.05). However, no significant associations were found between KAI1 and nm23 expression and clinical characteristics of LSCC (sex, age, disease position, differentiation, and T-stage).ConclusionsBoth KAI1 and nm23 can inhibit lymphangiogenesis and lymphatic metastasis in LSCC.

High expression of long non‑coding HOTAIR correlated with hepatocarcinogenesis and metastasis.

HOX transcript antisense RNA (HOTAIR), a newly discovered long noncoding RNA (lncRNA), has been reported to be a poor prognostic marker in many types of cancers. The current study attempted to investigate the biological roles and clinicopathlogical implications of HOTAIR in hepatocellular carcinoma (HCC), as well as understand the molecular mechanisms of HOTAIR in HCC progression. HOTAIR expression in 95 HCC patients with paired HCC tissues and adjacent non‑cancer tissues were investigated using quantitative reverse transcription‑polymerase chain reaction. The association between HOTAIR expression and clinicopathological features was assessed. The effects of HOTAIR were examined invitro assays by silencing the lncRNA. Pathway analyses were performed to illustrate the biological functions of the HOTAIR and coexpression genes. The expression level of HOTAIR was observed significantly higher in the HCC tissue than the adjacent non‑tumor tissue. HOTAIR expression levels were significantly higher in tumor samples from patients with distant metastasis, advanced stage, portal vein tumor embolus, vasoinvasion, tumor capsular infiltration or positive nm23 expression than those from patients without these conditions, correspondingly. The silencing of HOTAIR in liver cancer cells induced the inhibition of cell proliferation and promotion of apoptosis. Several pathways such as extracellular matrix‑receptor interaction, focal adhesion, pathways in cancer were annotated with the HOTAIR and coexpression genes. In summary, the present analysis indicates that HOTAIR might be an oncogene in HCC. It functions though promoting tumor cell growth and inhibiting apoptosis. HOTAIR may potentially be involved in HCC metastatic progression by several pathways correlated to cell adhesion, and may be a therapeutic target in future.

RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway.

The Nm23 metastasis suppressor family is involved in physiological and pathological processes including tumorigenesis and metastasis. Although the inverse correlation of Nm23 level with tumor metastasis potential has been widely observed, the mechanisms that regulate the expression of Nm23 remain poorly understood. Our previous studies have revealed that Nm23-H1/2 isoforms are upregulated by RGS19, a regulator of G protein signaling (RGS) protein which accelerates the termination of Gi signals. Here, we examined the ability of RGS19 to stimulate transcriptional regulation of Nm23 by screening a panel of luciferase reporter genes. Transient and stable overexpression of RGS19 upregulated the Nm23-H1/2 protein levels and activated several transcription factors including CREB, AP-1 and SRE in HEK293 cells. Interestingly, agents that increase the intracellular cAMP level and the phosphorylation of CREB (e.g., adrenergic receptor agonist, forskolin, and cAMP analogues) upregulated the expression of Nm23-H1/2 in HEK293 cells and several cancer cell lines including A549, HeLa, MDA-MB-231, and MDA-MB-435s cells. Conversely, inhibition of protein kinase A (PKA) by H-89 suppressed the phosphorylation of CREB and reduced the expression of Nm23-H1/2. Furthermore, activation of PKA attenuated cancer cell migration in wound healing and transwell assays. Collectively, these results revealed a PKA-dependent mechanism for controlling Nm23-H1/2 expression.