Molecular mechanism of inflammatory action in promoting tumors

Over the past ten years studies in animals and human have supported the links between inflammation and tumors. The inflammatory cells and agents found in tumors play an important role in the pathogenesis of malignant disease facilitating tumor growth, invasion and metastasis. This article reviewed the molecular mechanism of inflammatory action in promoting tumors and suggested that inflammatory cytokine network is more likely to contribute to immunosuppression than to mount an effective host anti-tumor response.     

Tumor stem cells and glioma initiating cells

The tumor stem cell theory supposed that tumor stem cells are the origin of tumor abnormal proliferation, invasion, metastasis, drug resistance and recurrence. As the theory is put forward, it redefines the functions of classic stem cells in tumorigenesis. It is a great event for recent studies on glioma initiating cells as brain tumor stem cells were identified and isolated successfully. A lot of evidence from experiments in vivo and in vitro demonstrates that brain tumor stem cells might play an important role in glioma tumorigenesis. In this review, we discuss the relationship between tumor stem cells and tumorigenesis, and the research on the correlation between brain tumor stem cells and glioma genesis.     

Expression of Survivin and its relationship to prognosis in human hepatocellular carcinoma

AIM: To study the expression of Survivin and its relationship to prognosis in human hepatocellular carcinoma(HCC).METHODS: The expression of Survivin protein in 83 cases of HCC and their neighboring noncancerous tissues was detected by immunohistochemistry.The expression of Survivin mRNA in 11 cases of HCC and their neighboring noncancerous tissues was detected by semi-quantitative RT-PCR.RESULTS: Survivin protein expression was detected in 53 of 83 (63.9%) HCC tissues and 21 of 53 (39.6%) corresponding noncancerous tissues.22 of 53 Survivin-positive HCCs (41.5%) showed punctate nuclear staining in HCC cells,24 of 53 Survivin-positive HCCs (45.3%) showed cytoplasmic staining in HCC cells and the remaining 7 showed both nuclear and cytoplasmic staining.The positive rates of nuclear Survivin expression in cases of envelope invasion or tumor metastasis were significantly higher than those in cases without envelope invasion or tumor metastasis (P<0.05).The patients with positive nuclear Survivin expression had the higher chance of poor prognosis than those with negative nuclear Survivin expression (P<0.01).Survivin mRNA was detected in all the 11 HCC and 5 of 11 (45.5%) neighboring noncancerous tissues.CONCLUSION: There is a high expression of Survivin in HCC and positive nuclear Survivin may play an important role in malignant biological behavior and prognosis of HCC.     

Expression of GATA3 in human breast cancer tissues and its clinical significance

AIM: To investigate the expression of GATA3 in human breast carcinoma and its clinical significance. METHODS: The expression level of GATA3 in breast cancer tissues from 124 patients was detected by the method of immunohistochemistry and the relationships between GATA3 expression and other clinicopathological factors were analyzed. RESULTS: Low expression of GATA3 in breast cancer tissues was associated with estrogen receptor (ER)/progesterone receptor (PR) negative, high histological tumor grade, p53 mutation and vascular invasion (P<005), but not with age, tumor size,human epidermal growth factor receptor 2 (HER-2) expression and lymph node metastasis (P>005). In all breast cancer tissues, the positive expression rate of GATA3 was 56.4%. The positive expression rate of GATA3 in luminal breast cancer is 684%, higher than that in non-luminal breast cancer (326%, P<005). In all breast cancer tissues, the expression of GATA3 in middle recurrence risk group was higher than that in high recurrence risk group (P<005). CONCLUSION: GATA3 expression in breast cancer is related to differentiation and biological characteristics of the tumor, which can be a factor for evaluation of the treatment and prognosis.     

Effect of phosphatidylinositol 3-kinase in angiogenesis-related diseases

Angiogenesis is involved in the pathological processes such as wound healing, atherosclerosis, rheumatoid arthritis and tumor, in which the pathogenesis and development are closely related to the new blood vessel formation. Phosphatidylinositol 3-kinase (PI3K), one of the important intracellular signaling proteins, mediates many signal transductions in cell migration, proliferation and angiogenesis. The activity of PI3K and its signaling pathway play a unique role in atherogenesis, unstability of atherosclerotic plaque, tumor metastasis and recurrence, etc. This review summarizes the effect of PI3K in angiogenesis-related diseases.     

Expression of miR-143 and its clinicopathologic significance in gastric cancer

AIM: To investigate the expression of miR-143 and its association with clinicopathologic features in gastric cancer.METHODS: The expression level of miR-143 in 32 cases of gastric cancer and matched non-tumor adjacent tissue specimens was examined using stem-loop real-time RT-PCR. The relationship between the expression of miR-143 and its clinicopathologic features of gastric cancer was analyzed.RESULTS: The expression level of miR-143 was significantly lower in the tumor tissues than that in the adjacent tissues (P<0.05). Down-regulated miR-143 expression was associated with the cell differentiation (P<0.05) and lymph node metastasis (P<0.05) in gastric cancer patients. No significant association was found between the expression of miR-143 and the status of gender, age, blood type, tumor location, tumor size, depth of tumor invasion and tumor node metastasis stage.CONCLUSION: It is possible that miR-143 plays an important role in the generation and progression of gastric cancer. The expression level of miR-143 may be a valuable adjuvant parameter for predicting the poorly differentiated gastric cancer.     

Relationship between tumor metastasis suppressor gene KAI1 and the invasive and metastatic characteristics of osteosarcoma

AIM:To study the expression of metastasis suppressor gene KAI1 mRNA in osteosarcoma tissue and osteosarcoma cell lines,and the relationship between it and the biological behavior of the tumor cells.METHODS:RT-PCR was used to detect KAI1 mRNA in 18 cases of resected fresh osteosarcoma samples and three cultured osteosarcoma cell lines.The proliferative rate,the adhesive and invasive abilities of the 3 cell lines were detected.The results were treated by analysis system of images and analyzed with t test.RESULTS:The relative amount of KAI1 mRNA in osteosarcomas with lung metastasis was 0.80±0.50,while that was 1.48±0.64 in osteosarcomas without lung metastasis,the former was significantly lower than the latter (P<0.05).However,KAI1 mRNA had no corelation with the recurrence of osteosarcoma.The expression of KAI1 mRNA in U2-OS was highest (P<0.05),while the proliferation rate,the adhesive and invasive ability of U2-OS were the lowest among the 3 cell lines (P<0.01).CONCLUSION:The metastasis suppressor gene KAI1 might take part in influencing the lung metastasis of osteosarcoma,which might be caused by inhibiting the tumor cell proliferation,adhesion and invasion.     

Expression and clinical significance of PAK4 in non-small cell lung cancer

AIM: To investigate the expression and clinical significance of PAK4 in the cell lines and tissues of non-small cell lung cancer (NSCLC). METHODS: PAK4 expression in human bronchial epithelial (HBE) cells, NSCLC cell lines, NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry, real-time PCR and Western blot. Prognostic value of PAK4 expression was evaluated by Kaplan-Meier analysis and Cox regression. RESULTS: PAK4 was over-expressed in the NSCLC cell lines at both mRNA and protein levels compared with HBE cells (P<0.05). PAK4 was over-expressed in the NSCLC tissues at both mRNA and protein levels compared with adjacent non-tumor tissues (P<0.05). PAK4 was over-expressed in the metastatic NSCLC tissues compared with the primary NSCLC tissues (P<0.05). Higher PAK4 staining scores were positively correlated with differentiation, lymph node metastasis, distant metastasis, and clinical stage. Kaplan-Meier analysis and log-rank test showed that overall survival was significantly different between the patients with up-regulated PAK4 and the patients with down-regulated PAK4(P<0.05). PAK4 over-expression was associated with NSCLC progression.CONCLUSION: Increased PAK4 expression was associated with tumor invasion, metastasis and prognosis in the patients with NSCLC. PAK4 is an important prognostic marker and potential therapeutic target in NSCLC.     

Differentiated expression of myosin VI in diverse human carcinomas

AIM: To investigate the expression profile of myosin VI in various human carcinomas and adjacent normal tissues. METHODS: A piece of cancer profiling array containing 154 matched cDNA pairs from 19 tumors and the adjacent normal tissues and 10 diverse tumor cell lines were separately hybridized with radiolabeled probes for myosin VI and housekeeping gene ubiquitin. Immunohistochemistry (IHC) was used to confirm the expression profile of myosin VI in 40 cases of ovarian adjacent normal tissues, 8 cases of cystadenoma, 16 cases of borderline tumors and 52 cases of endometrioid carcinoma by tissue microarray. RESULTS: Myosin VI was expressed in all the tissues and cell lines. The expression of myosin VI was significantly higher in ovarian and colon cancer tissues than that in matched normal tissues. The results of IHC confirmed that myosin VI expression rates were 100% (52/52), 81.3% (13/16) and 10.4% (5/48) in the ovarain carcinoma, boderline tumor and nomal ovarian epithelium or cystadenoma, respectively. The expression of myosin VI protein was significantly higher and stronger in ovarain carcinoma than that in the borderline tumor, benign tumor or normal ovary tissues. A significant correlation was also found between the expression of myosin VI and the tumor grade of ovarain carcinoma. CONCLUSION: Differentiated expression of myosin VI is found in diverse malignant tumor tissues and cell lines, suggesting myosin VI plays an important role in the tumor development and progression.     

Clinical significance of LN/LN-R expression in nasal and paranasal sinus malignant tumor

AIM: To study the clinical significance of laminin/laminin receptor(LN/LN-R) expression in nasal and paranasal sinus malignant tumor(NPMT).METHODS: The immunohistochemical technique was used to detect the expression of LN and LN-R in 137 cases of NPMT, 78 cases of para-cancer tissues and 37 cases of non-cancer tissues.RESULTS: The positive rate of LN in NPMT(13.87%) was significantly lower than that in para-cancer tissues(87.18%) and non-cancer tissues(72.97%), and the positive rate of LN-R in nasal inverting papilloma(76.47%) was significantly higher than that in NPMT(28.47%), para-cancer tissues(10.26%) and nasal polypus and cyst tissues(10.0%). A significant difference of LN-R expression, but not LN, between endepidermis and soft tissue of the NPMT was observed(P<0.01). CONCLUSION: Decrease in LN expression provides the essential condition for the invasion and metastasis of the malignant tumor. Determining the expression level of LN in NMPT will be helpful for evaluation of tumor development and clinical management. High expression of LN-R only in the nasal inverting papilloma indicates that LN-R may play different roles in different pathotypes of NPMT.     

Methylation of TIMP-3 gene and their relationships with their clinical-pathological characteristics of colorectal cancers

AIM: To investigate whether methylation of the TIMP-3 gene is associated with clinical-pathological characteristics, recurrence and metastasis of the colorectal cancer. METHODS: Nest methylation specific PCR (nMSP) and RT-PCR techniques were used to detect methylation of TIMP-3 gene and its mRNA expression in the colorectal cancer specimen and adjacent non-cancerous tissues. RESULTS: The expression of TIMP-3 mRNA in tumor tissues was distinctly reduced (P<0.01). The expression of TIMP-3 mRNA in those without lymph node metastasis was higher than those with lymph node metastasis (P<0.01). The patients with Duke's C, D and lymph node metastasis were more to contain methylated TIMP-3 compared to those with Duke's A, B and no lymph node metastasis (P<0.05). Statistical differences in pathological characteristics such as tumor site, Duke's stage, histological differentiation and type between TIMP-3 methylation positive group and negative group were observed (P<0.05). CONCLUSION: Methylation of the TIMP-3 gene promoter usually occurs in the proximal site, infiltrating type, poor cellular differentiation, lymph node metastasis and advanced stage of colorectal cancers patients.     

DNA ploidy analysis and the expression of TIMP-2 and E-cadherin in gastric carcinoma

AIM:To investigate DNA ploidy and the expression of TIMP-2 and E-cadherin in gastric carcinoma in order to understand its molecular basis and probable mechanism of invasion and metastasis. METHODS:Immunohistochemical methods were used to detect the expression for TIMP-2 and E-cadherin in 99 cases of gastric carcinoma, 16 cases of adjacent noncancerous mucosa, 16 cases of distant metastases and 25 cases of metastatic lymph nodes. Flow cytometry DNA ploidy and S-phase fraction (SPF) analysis was performed on 47 cases of gastric cancer, 6 cases of adjacent noncancerous mucosa and 4 cases of distant metastasis cancer with the use of formalin-fixed paraffin embedded specimens. RESULTS:The expression of TIMP-2 was significantly correlated with Borrmann’s classification, LN metastasis and the depth of invasion. The expression of E-cadherin was significantly correlated with tumor cell differentiation, Lauren’s classification, Borrmann’s classification, LN metastasis and the depth of invasion. There was a positive relationship between DNA aneuploid rate and differentiation and LN metastasis. There was a positive relationship between SPF that is higher than 15% and tumor size, differentiation and LN metastasis. And there was a significantly difference between carcinoma and noncarcinoma when the expression of E-cadherin, DNA aneuploid rate and SPF were analyzed. There was no correlation between TIMP-2 and E-cadherin. There was a positive relationship between DNA ploidy or SPF and the expression of E-cadherin. CONCLUSION:As the development of tumor progression and heterogeneity, the abnormal expression of TIMP-2 or E-cadherin or the rate of DNA aneupoid or higher SPF gradually correspondingly increases, suggesting that they play a crucial role in gastric carcinoma progression. Furthermore, each factor influences one another and further accelerates the process of tumor progression.     

Long noncoding RNA MALAT1 regulates Rac1b expression and is associated with colorectal cancer metastasis

AIM: To investigate the role of MALAT1 in colorectal cancer metastasis.METHODS: The mRNA expression levels of MALAT1 and Rac1b in the tumor and adjacent normal tissues were examined by real-time PCR. MALAT1 was knocked down by siRNA in colorectal cancer cell lines. The expression of Rac1b and the epithelial-mesenchymal transition markers was examined by Western blot. Cell proliferation was determined by EdU analysis. The effects of MALAT1 on the cell migration and invasion were examined by Transwell assay. RESULTS: The expression of MALAT1 was down-regulated in colorectal cancer. Down-regulation of MALAT1 induced Rac1b overexpression, which in turn increased the expression levels of E-cadherin and β-catenin. Furthermore, down-regulation of MALAT1 promoted the cell proliferation, invasion and migration. CONCLUSION: MALAT1 is associated with metastasis of colorectal cancer through regulating the expression of Rac1b and the downstream factors.     

PTEN and signal transduction and tumor

PTEN is a candidate tumor suppressor which has sequence homology withdual-specifici-ty phosphatase. PTEN is a multifunctional protein endowed with a phosphatase activity capable of dephosphory-lating both tyrosine phosphate, serine/threonine phosphate residues on proteins and phospholipids of the phosphati dylinositol pathway. PTEN appears to be mutated at considerable frequency in several types of humantumors, including those frombrain, breast, endometrium, and prostate. PTEN play an important role in pathogenesis of tumor, tumor cell invasion and metastasis. In this review, we will discuss the chemical structure of PTEN, its phosphatase activity, the ability of affecting signal transduction, and its mutational status in cancer.     

P-selectin on activated platelets promotes hematogenous metastasis of primary lung cancer via P-selectin glycoprotein ligand-1

AIM: To investigate the relationship between platelets/P-selectin on activated platelets and clinico-pathological features, hematogenous metastasis and prognosis of lung cancer, and to explore the effect of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) interaction on the hematogenous metastasis-related integrin β3 (ITGB3). METHODS: The expression of P-selectin on activated platelets was detected by flow cytometry, and its effects on lung cancer and the risk of hematogenous metastasis were analyzed. The expression of PSGL-1 in different types of lung cancer tissues and cell lines was determined by Western blot. By co-culturing platelets and lung cancer cells in vitro, the effects of up- and down-regulation of PSGL-1 on invasion and migration abilities of lung cancer cells were observed. RESULTS: The peripheral blood platelet counts and P-selectin expression on activated platelets in the patients with lung cancer were significantly increased (P<0.05). The P-selectin expression on activated platelets was significantly associated with hematogenous metastasis of lung cancer (r=0.256, P<0.05). The strongest expression of PSGL-1 was found in the lung adenocarcinoma samples, next in the lung squamous-cell carcinoma samples, and the weakest in small-cell lung cancer samples. P-selectin promoted transmembrane invasion of lung cancer cells. Inhibition of P-selectin and its ligand PSGL-1 reduced ITGB3 expression, invasion and migration of lung cancer cells. CONCLUSION: The P-selectin level on activated platelets is significantly associated with hematogenous metastasis of lung cancer, which is related to the binding of P-selectin and its ligand PSGL-1. Up-regulation of ITGB3 level after their binding might be one of the mechanisms of the remodeling of extracellular matrix to facilitate hematogenous metastasis of lung cancer.     

Relationship between activity of matrix metalloproteinases-2 and invasion,metastasis of breast cancer

AIM: To investigate relationship between activity of matrix metalloproteinases-2 (MMP-2, 72 kD) and invasion, metastasis of breast cancer. METHODS: Useing zymography and computer software assisted analysis, the activitive levels of MMP-2 (72 kD) in tissues from breast cancer were measeured. RESULTS: Mean activitive levels of MMP-2 72 kD (13.93±3.60) in breast cancer were lower than those in benign disease (21.43±8.31), P<0.05. There was no difference (P>0.05) in MMP-2 62 kD+72 kD of benign and malignant disease, but MMP-2 62 kD (13.83±4.53) and MMP-2 62 kD/62 kD+72 kD(0.48) respectively were significantly higher in malignant disease (P<0.01). It was also found that MMP-2 62 kD/62 kD+72 kD were apparently higher in invasive carcinomas (0.48) and lymph node metastases (0.61), P<0.01, respectively. CONCLUSION: These results demonstrated that a clear relationship between MMP-2 activity and the invasion and metastasis of breast carcinoma.     

Advances of phosphatase of regenerating liver-3 in hematological malignancies

In recent years,accumulating evidence shows that phosphatase of regenerating liver-3(PRL-3) is closely implicated in tumor progression,especially in the stages of invasion and metastasis of various solid tumors,including colorectal cancer,gastric cancer and breast cancer.However,the study of PRL-3 in hematological malignancies is relatively lagged, but there are some advances in leukemia and myeloma,in which PRL-3 up-regulation is tightly associated with poor prognosis,while the underlying mechanism of signal transduction is gradually explored.In this review,we summarized the recent advances of PRL-3 in hematological malignancies such as acute myeloid leukemia,multiple myeloma and chronic myeloid leukemia,as well as the molecular mechanism of PRL-3 in pathogenesis.     

Relationship between expression of MKK-4 and MMP-9 genes in primary hepatic carcinoma with or without invasion and metastasis

AIM：To investigate the expression of mitogen activated protein kinase kinase 4 (MKK-4) and MMP-9 mRNA in primary hepatic carcinoma (PHC), and to analyze its relationship with invasion and metastasis. METHODS：The expression of MKK-4 and MMP-9 mRNA in 34 cases of hepatic carcinoma tissues and adjacent tissues,and in 12 cases of normal liver tissues were detected with RT-PCR. RESULTS：(1) The expression level of MMP-9 mRNA was higher in metastatic cancer tissues than that in other tissuses (P<0.01). (2) There was significant statistical difference among the expression level of MKK-4 mRNA, but the level in metastatic cancer was low (P<0.01). (3) There was no statistical difference among the expression level of MKK-4 or MMP-9 mRNA among the adjacent tissues and normal tissues (P>0.05). (4) MMP-9 mRNA had a tendency to rise as PHC became invasive and metastatic.The expression level of MKK-4 had a tendency to decline in PHC became invasive and metastatic. (5) The expression level of MMP-9 or MKK-4 mRNA had no correlations with tumor volume,or cell differentiation (P>0.05). (6) There were correlations between expressions of MKK-4 and MMP-9 mRNA in PHC (Pearson Correlation, r=-0.925, P<0.01). CONCLUSION：There are high MMP-9 mRNA expression and low MKK-4 mRNA expression in PHC.The expression level of MKK-4 or MMP-9 mRNA is correlated with tumor metastasis.     

Methylation status of multiple genes in colorectal cancer tissues and its clinical significance

AIM: The aim of the present study was to detect the methylation status of multiple genes (Syk, CDH1 and TIMP-3) in colorectal cancer (CRC) tissues, to investigate the roles in the pathogenesis of CRC, to investigate whether methylation of multiple genes was associated with recurrence and metastasis of CRC, and to evaluate its ability to predict the prognosis of CRC. METHODS: Nested methylation-specific PCR (n-MSP) were used to detect methylation status of spleen tyrosine kinase (Syk) from 120 CRC tissues and the methylation status of CDH1 and tissue inhibitor of metalloproteinase-3 (TIMP-3) from 100 CRC tissues. RESULTS: We found that methylation in one or more genes, co-methylation in two genes and three genes were detected in 74%, 21%, and 8% of CRC tissues. No significant correlation between three genes co-methylation and lymph node metastasis (2=0.725,P>0.05) was observed. The methylation of CDH1 gene, but not Syk or TIMP-3 gene, was significantly related with liver and lung metastasis of CRC (2=6.938,P<0.01). The methylation of Syk or TIMP-3, and co-methylation of CDH1 and TIMP-3 were risk factors in the prognosis of colorectal cancer after surgical treatment, and three genes co-methylation was not a risk factor. CONCLUSION: Our results indicate that methylation of multiple genes exists in CRC tissues. The methylation of multiple genes is not a necessary factor in the pathogenesis, metastasis and recurrence of CRC, and also it is not a necessary prognostic factor in CRC.     

Relationship between expression level of TIMP-3 and invasion/metastasis of hepatocellular carcinoma

AIM: To detect the levels of tissue inhibitor of metalloproteinase-3 (TIMP-3) in both plasma and the tissue of hepatocellular carcinoma (HCC), and to elucidate their association with clinical features.METHODS: Plasma protein levels of TIMP-3 in 56 HCC patients and 30 cases of controls were detected by ELISA.The mRNA and protein levels of TIMP-3 in 30 HCC tissue samples with their portal vein tumor embolus and lymphatic metastasis tissues, and in normal liver tissues from 30 controls were detected by RT-PCR and Western blotting.The relationship between mRNA and protein levels and their clinic-pathological data were analyzed.RESULTS: The plasma TIMP-3 protein levels in the extrahepatic metastasis patients were obviously lower than those in the non-extrahepatic metastasis patients (P<0.05).The mRNA levels of TIMP-3 in normal liver, carcinoma in situ, portal vein tumor embolus and lymphatic metastasis tissues were 0.78±0.09, 0.52±0.09, 0.42±0.07 and 0.40±0.08, respectively, with significant differences among them (P<0.05).The protein levels of TIMP-3 in these 4 kinds of tissues were 115.08±8.60, 77.04±8.83, 64.43±3.80 and 62.80±3.73, respectively, also with significant differences among them (P<0.05).CONCLUSION: The expression of TIMP-3 significantly decreases in the carcinoma in situ tissues of HCC patients, and decreases more obviously in the portal vein tumor embolus and lymphatic metastasis tissues, indicating that low expression of TIMP-3 may play an important role in HCC invasiveness and metastasis.