Cellular Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) belongs to the death effector domain superfamily, which is important in regulating apoptosis and proliferation. c-FLIP inhibits the extrinsic recep-tor-mediated apoptotic pathways and intrinsic mitochondrial apoptotic pathways through competition with caspase-8 for recruitment to Fas-associated death domain protein. Moreover, the cleavage products (i.e., p43-FLIP fragment and p22-FLIP fragment) directly acti-vate NF-κΒ, Erk survival signaling, and other non-apoptotic signaling pathways. The c-FLIP (L) can function either as an anti-apoptotic molecule, in a way analogous to c-FLIP (S) and c-FLIP (R), or as a pro-apoptotic molecule to facilitate the activation of caspase-8 at the death-induced signaling complex. The identified dual functionality of c-FLIP depends on various factors, including its expression level, interaction with caspase-8, and its subcellular localization. c-FLIP is frequently over-expressed in many different tumor types, and con-tributes to tumor cell immune surveillance, chemotherapy resistance, and apoptosis-resistance induced by TNFα, TRAIL, and FasL. Fur-thermore, c-FLIP is essential in obtaining aggressive biological behaviors, and is useful in predicting the prognosis of patients with vari-ous malignant tumors. This review focuses on the molecular mechanisms that control the dual regulation of c-FLIP in life/death deci-sion at death-induced signaling complex. Increasing evidence supports the function of c-FLIP as a tumor therapeutic marker to restore an apoptotic response for TRAIL therapy in cancers. Insight into these processes will improve our understanding of apoptosis, and pro-vide new approaches for rational treatment strategies.

Neovascularization is the fundamental process during tumorigenesis and tumor malignant progression. According the traditional neovascularization theory, tumor vasculatures are mainly developed through angiogenesis by sprouting from preexisting ves-sels and vasculogenesis via recruitment of endothelial progenitor cells from the bone marrow, and the endothelial-dependant vessels are the only way that provides tumor with blood. However, more and more studies indicate that tumor microcirculation network is heteroge-neous and cancer stem cells (CSCs) play an important role during tumor neovascularization. This review highlights the contribution of CSCs to tumor microcirculation modes and the potential anti-angiogenesis targets. Furthermore, this review presents insights for perti-nent studies in the future.

Given the unlimited proliferation and aerobic glycolysis in tumor cells, these cells require more glucose, glutamine, and other nutrients compared with normal cells. Tumor cells are often affected by insufficient nutrient supply. However, by sensing changes in the nutrient supply in tumor microenvironment and by regulating signal-transduction pathways, some specific proteins can help tumor cells in blocking the cell cycle, reprogramming metabolism, and regulating autophagy to progress and survive against nutri-ent stress. Exciting innovations have been made to elucidate the mechanisms relevant to this process. This review aims to highlight re-cent studies on the mechanisms of sensing the low nutrient supply in microenvironments, as well as the downstream effect factors in cancer cells.

Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Most lncRNAs have pro-nounced oncogenic effects associated with tumorigenesis and progression, promoting the proliferation, migration, invasion, and me-tastasis of tumor cells. The specific lncRNAs expression in particular types of cancers makes them promising diagnostic and prognostic biomarkers. Currently, studies on lncRNAs expression, functions, and mechanisms have attracted considerable attention in cancer re-search. However, these studies mainly focus on epitheliogenic malignant tumors. In this review, we outline the current state of infor-mation on lncRNAs and research progress on its role in haematopoietic and lymphoid tissue tumors.

Ovarian epithelial carcinomas are the most common lethal gynecological malignancies. Ovarian carcinomas are divid-ed into Types I and II based on different morphologies, genetic alterations, and biomarker expression. Low-grade micropapillary serous carcinoma are Type I tumors. Type I tumors are slow growing, generally confined to the ovary at diagnosis, and with better prognosis. These tumors develop from well established precursor lesions that are termedborderlinetumors. Type 1 tumors are genetically stable and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN, and beta-catenin. Type II tumors are rapidly growing and highly aggressive neoplasms, for which well defined precursor lesions have not been described. They may arise in the fimbrial epithelium of the oviduct with advanced stage, more aggressive behavior, and worse prognosis. High-grade serous carcino-ma belongs to Type II tumors. This group of tumors has a high level of genetic instability and is characterized by TP53 mutation. Hence, ovarian cancer comprises a heterogeneous group of tumors with distinctly different histological characteristics, molecular genet-ic features, and clinical course.

Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type family, is a broad-spectrum serine proteinase inhibitor. The expression of TFPI-2 is inversely related to increasing degree of malignancy, suggesting a role of TFPI-2 in the mainte-nance of tumor stability and inhibition of the growth of neoplasma. Aberrant methylation of TFPI-2 promoter cytosine-phosphorothio-ate-guanine (CpG) islands has been widely documented to be responsible for diminished expression of TFPI-2 mRNA and protein dur-ing cancer progression. TFPI-2 expression is significantly up-regulated by the ERK1/2 and JNK signaling pathways and modestly in-creased by VEGF, TNF-alpha, and fibroblast growth factor in time-and dose-dependent manners. TFPI-2 can maintain the stability of the tumor environment and inhibit invasiveness and growth of neoplasms. TFPI-2 has also been shown to regulate proliferation, apopto-sis, and vasculogenic mimicry of tumor cells, which may contribute significantly to tumor growth inhibition. Restoration of TFPI-2 ex-pression in tumor tissue inhibits tumor growth and metastasis, which creates a novel possibility of cancer patient treatment. This review focuses on the expression and the molecular regulation mechanisms of TFPI-2 in malignant tumors that control the functions of TFPI-2 in proliferation, apoptosis, and angiogenesis. Insight into these processes will improve our understanding of TFPI-2 and provide new ap-proaches for rational treatment strategies.

Objective:To clarify the effect of voltage-gated proton channel 1 (Hv1) on the migration and invasion of breast cancer cells. Methods:The protein expression of Hv1 was detected in human breast cancer cell lines with different metastatic abilities. SiRNA technique was used to down-regulate the expression of Hvl in breast cancer MDA-MB-231 cells. Scratch and matrigel invasion methods were used to observe the effect of Hvl on the migration and invasion of breast cancer cells, and the relevant molecular mechanism was explored. Results:Hv1 was highly expressed in the highly metastatic breast cancer cell line MDA-MB-231. Hvl was more highly expressed in MDA-MB-231 cells with higher metastatic ability. The SiRNA sequence target at Hvl inhibited Hvl expression. Scratch and matrigel invasion experiments showed that the migration and invasion of MDA-MB-231 cells were significantly attenuated when Hv1 was knocked down by siRNA targeting Hv1. Zymography experiment on matrix metalloproteinase indicated that the enzyme activities of MMP-2 markedly decreased. Conclusion:Hv1 promoted the migration and invasion ability of breast cancer cells.

Objective: To investigate the relationship of loss of P16 expression with biologlical behaviors and prognosis of gastrointestinal stromal tumors(GISTs). Methods: The expression of P16 protein and mRNA was detected in GISTs tissues by immunohistochemistry,Western blot and RT-PCR.The prognosis was evaluated through follow up. Results: The expression rates of P16 protein and mRNA in GISTs were 53.8%(21/39，Frozen tissue)，51.3%(20/39，Frozen tissues)and 51.4%(37/72，Paraffin-embedded tissues)，respectively.The expression of P16 was significantly different among GISTs of different aggressive risk(P<0.05).With the incease of aggressive risk，the expression of P16 was deceased.The expression of P16 was negtively correlated with Ki-67 and patient survival(P<0.05). Conclusion: The loss of P16 expression has a positive correlation with the infiltration and progression of GIST.Detection of P16 protein and mRNA is helpful for the evalutaion of biological behaviors and prognosis of gastrointestinal stromal tumors.

Objective To investigate the effects of interferon-gamma (IFN-γ) on migration,invasion and vasculogenic mimicry (VM) formation of human melanoma cell line MUM-2B. Methods MUM-2B cells were divided into three groups, control group (10%FBS in DMEM), treatment group1 (10μg/L IFN-γ) and treatment group2 (100μg/L IFN-γ). Different concentrations of IFN-γ were added in the culture medium of MUM-2B cells. Wound-healing assay and matrigel invasion assay were performed to examine the migration and invasion ability of MUM-2B cells. Three-D culture was used to observe the VM formation. The expression of vascular endothelial growth factor (VEGF) of MUM-2B cells was detected by Western blot assay. Results The result of wound-healing assay showed that the migration distance of cells was decreased in treatment groups compared with that of control group. The migration distance of cells was decreased in treatment group 2 compared with that of treatment group 1(P＜0.05). The result of matrigel invasion assay showed that the number of invaded cells was decreased in treatment groups compared with that of control group, and which was significantly decreased in treatment group2 than that of treatment group1 (P＜0.05). The result of 3-D culture showed that cells in control group can form typical VM tube-like structures, whereas cells in treatment groups cannot. Western blot assay showed that the expression of VEGF protein was significantly decreased in treatment groups compared with that of control group, and the expression of VEGF protein was significantly decreased in treatment group2 than that of treatment group 1(P＜0.05). Conclusion These data suggest that IFN-γinhibits migration and invasion of MUM-2B cells, and inhibits VM formation by down regulating VEGF expression in vitro.

Objective:To investigate the inhibitory effect of Dickkopf-1 (Dkk1) on vasculogenic mimicry (VM) formation and the relevant mechanism. Methods:CD34-PAS dual staining and immunohistochemical staining were used to detect and analyze the re-lationship between VM existence and Dkk1 expression in 217 human colon cancer tissue samples;three dimensional (3D) culture was used to detect the influence of Dkk1 on tube structure formation and on VE-cadherin expression;a subcutaneous mouse xenograft mod-el was made to further validate the inhibitory role of Dkk1 on VM formation in vivo. Results:VM-positive samples indicated a lower expression of Dkk1(P<0.05);colon cancer cells with Dkk1 overexpression exhibited a decreased ability to form tube-like structure and a decreased expression of VE-cadherin;Dkk1 inhibited the VM-formation abilities of human colorectal carcinoma cell line xenograft tu-mor tissue. Conclusion:Dkk1 inhibits the VM formation of colon cancer.