ZDHHC12-mediated claudin-3 -palmitoylation determines ovarian cancer progression

The membrane protein claudin-3 (CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both and Of interest, CLDN3 undergoes -palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3 Moreover, the deprivation of -palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins. Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis Thus, our work reveals -palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 -palmitoylation might be a potential strategy for ovarian cancer therapy.

Cellular senescence and cancer progression / 国际儿科学杂志

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation.However,accumulating evidence show that senescent cells can have deleterious effects on the tissue microenvironment.The most significance of these effects is the acquisition of a senescenceassociated secretory phenotype (SASP) that could promote tumor progression.Even with our currently limited knowledge of the SASP and its potential effects on carcinogenesis,promising new strategies for cancer therapies are possible.

The oncogenic effects of p53-inducible gene 3 (PIG3) in colon cancer cells

The p53-inducible gene 3 (PIG3), initially identified as a gene downstream of p53, plays an important role in the apoptotic process triggered by p53-mediated reactive oxygen species (ROS) production. Recently, several studies have suggested that PIG3 may play a role in various types of cancer. However, the functional significance of PIG3 in cancer remains unclear. Here, we found that PIG3 was highly expressed in human colon cancer cell lines compared to normal colonderived fibroblasts. Therefore, we attempted to elucidate the functional role of PIG3 in colon cancer. PIG3 overexpression increases the colony formation, migration and invasion ability of HCT116 colon cancer cells. Conversely, these tumorigenic abilities were significantly decreased in in vitro studies with PIG3 knockdown HCT116 cells. PIG3 knockdown also attenuated the growth of mouse xenograft tumors. These results demonstrate that PIG3 is associated with the tumorigenic potential of cancer cells, both in vitro and in vivo, and could play a key oncogenic role in colon cancer.

Advances in competing endogenous RNA modulation of cancer progression / 肿瘤研究与临床

Protein-coding transcriptome,pseudogenes,long non-coding RNAs and circular RNAs can act as competing endogenous RNA (ceRNA).ceRNA can crosstalk with each other through microRNA recognition elements (MRE),thus regulating the post-transcriptional gene expression.More and more evidences showed that ceRNA could form an extensive network of post-transcription regulation,keep the cell homeostasis and involve in the disease development and progression like tumorigenesis and cancer progression.Depending on up-regulation or down-regulation of different kinds of microRNA in different cells,ceRNA acts as either an oncogene or a tumor suppressor.ceRNA may have a great potential in cancer diagnosis and treatment.

Chemopreventive and chemotherapeutic effects of genistein, a soy isoflavone, upon cancer development and progression in preclinical animal models / 한국실험동물학회지

Genistein is one of isoflavones mostly derived in a leguminous plant. It is well known as one of phytoestrogens that have structures similar to the principal mammalian estrogen. It has diverse biological functions including chemopreventive properties against cancers. Anticancer efficacies of genistein have been related with the epidemiological observations indicating that the incidence of some cancers is much lower in Asia, where diets are rich in soyfoods, than Western countries. This review deals with in vivo anticancer activities of genistein identified in animal studies being divided into its effects on carcinogenesis and cancer progression. Because animal studies have advantages in designing the experiments to suit the goals, they imply diverse information on the anticancer activity of genistein. The in vivo animal studies have adopted the specific animal models according to a developmental stage of cancer to prove the anticancer efficacies of genistein against diverse types of cancer. The numerous previous studies insist that genistein effectively inhibits carcinogenesis in the DMBA-induced animal cancer models by reducing the incidence of adenocarcinoma and cancer progression in the transgenic and xenograft animal models by suppressing the tumor growth and metastatic transition. Although the protective effect of genistein against cancer has been controversial, genistein may be a candidate for chemoprevention of carcinogenesis and cancer progression and may deserve to be the central compound supporting the epidemiological evidence.

The Role of CTGF in Osteosarcoma Progression / 대한골관절종양학회지

PURPOSE: To examine the expression of Connective Tissue Growth Factor (CTGF) in osteosarcoma and to evaluate its role in osteosarcoma invasion and proliferation. MATERIALS AND METHODS: The mRNA expression of CTGF from 23 patient-derived osteosarcoma cell lines was examined, and the role of CTGF in cell invasion and proliferation was examined using siRNA transfection. RESULTS: The over-expression of CTGF mRNA was observed in 17 cell lines (74%). CTGF-specific siRNA transfection into SaOS-2 and MG63 cell lines resulted in efficient knockdown of CTGF expression on Western blot analysis. siRNA transfected cells showed decreased migration on Matrigel invasion assay and decreased cell proliferation on WST-1 assay. CONCLUSION: These results indicated that the CTGF expression may play an important role in osteosarcoma progression, and may be a therapeutic target of osteosarcoma.

From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers / 대한해부학회지

Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, efforts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting.

From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers / 대한해부학회지

Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, efforts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting.

Expression of erythropoietin and its receptor increases in colonic neoplastic progression: The role of hypoxia in tumorigenesis.

Background: Tissue hypoxia is a characteristic patho-physiologic property of colorectal cancer. This process may also add to a therapeutic problem of solid tumor resistance to chemo- and radiation therapy. Erythropoietin (Epo) expression is induced by tissue hypoxia. Acting via its receptor (EpoR), Epo inhibits apoptosis of erythroid cells and has been shown to rescue neurons from hypoxic damage. Increased Epo and EpoR expression has been recently described in human breast, renal and cervical carcinoma. Given the characteristic tumor diathesis present in majority of colorectal cancers, we examined whether Epo signaling may play a role in colonic neoplastic progression. Materials and Methods: Expression of Epo and EpoR was examined using immunohistochemistry in 24 cases of primary colorectal and metastatic adenocarcinomas versus adenomas and normal colonic mucosa. Immunohistochemical stains were evaluated semiquantitatively based on a four-tiered scale. Based on the combination of extent and intensity of immunoreactivity, an immunostaining score (0-300) was determined for each sample. Expression of Epo and EpoR protein and mRNA was examined using Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively, in both normal colonic tissue and carcinoma specimens in five cases. Results: Epo expression was sequentially increased in normal colonic mucosa (8.3 ± 5.6, mean ± SEM), adenoma (26.4 ± 9.1), primary carcinoma (96.1 ± 12.8) and metastatic carcinoma (122 ± 51.3). EpoR expression was also sequentially increased in normal colonic mucosa (22.3 ± 11.8), adenoma (108.7 ± 24.2), primary carcinoma (178.7 ± 16.6) and metastatic carcinoma (220 ± 58.3) (P< 0.05 for all results). Epo and EpoR showed enhanced expression in the areas adjacent to ischemia/necrosis. Western blot and RT-PCR analysis revealed increased EpoR protein and mRNA levels in carcinoma compared to normal mucosal colon specimens. Focal stromal Epo and EpoR immunoreactivity was present in 10 and 12 cases, respectively. Conclusions: The uniform increase in the expression of Epo and EpoR along the colonic neoplastic sequence and further increase in ischemic/necrotic areas indicates that the Epo signaling pathway is an important component in colon carcinogenesis including possible epithelial-stromal interactions.

Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property? / 한국실험동물학회지

Acting as hormone mimics or antagonists in the interaction with hormone receptors, endocrine disrupting chemicals (EDCs) have the potentials of disturbing the endocrine system in sex steroid hormone-controlled organs and tissues. These effects may lead to the disruption of major regulatory mechanisms, the onset of developmental disorders, and carcinogenesis. Especially, among diverse EDCs, xenoestrogens such as bisphenol A, dioxins, and di(2-ethylhexyl)phthalate, have been shown to activate estrogen receptors (ERs) and to modulate cellular functions induced by ERs. Furthermore, they appear to be closely related with carcinogenicity in estrogen-dependant cancers, including breast, ovary, and prostate cancers. In in vivo animal models, prenatal exposure to xenoestrogens changed the development of the mouse reproductive organs and increased the susceptibility to further carcinogenic exposure and tumor occurence in adults. Unlike EDCs, which are chemically synthesized, several phytoestrogens such as genistein and resveratrol showed chemopreventive effects on specific cancers by contending with ER binding and regulating normal ER action in target tissues of mice. These results support the notion that a diet containing high levels of phytoestrogens can have protective effects on estrogen-related diseases. In spite of the diverse evidences of EDCs and phytoestrogens on causation and prevention of estrogen-dependant cancers provided in this article, there are still disputable questions about the dose-response effect of EDCs or chemopreventive potentials of phytoestrogens. As a wide range of EDCs including phytoestrogens have been remarkably increasing in the environment with the rapid growth in our industrial society and more closely affecting human and wildlife, the potential risks of EDCs in endocrine disruption and carcinogenesis are important issues and needed to be verified in detail.

Las proteasas en la progresión neoplásica / Proteases in cancer progression

La invasión y la metástasis son los eventos más importantes en la progresión del cáncer, en los cuales están implicadas muchas moléculas, entre ellas, las proteasas. Éstas desempeñan un papel importante en etapas tempranas de la carcinogénesis, en la invasión, en fenómenos asociados como la angiogénesis y en la metástasis, principalmente por su capacidad para degradar componentes de la matriz extracelular, aunque sus sustratos son de naturaleza diversa: citocinas, quimiocinas, factores de crecimiento (b- FGF, HGF, VEGF) y de muerte celular, cistatina-C, galectina, procolágena y otras proteasas, que pueden favorecer o inhibir la progresión neoplásica. Las proteasas son también moléculas de señalización que modulan a otras moléculas; forman cascadas, circuitos e incluso redes, que en conjunto determinan parte del potencial maligno. Se sabe que tanto la célula tumoral como las del estroma secretan diversos factores que regulan directa e indirectamente la expresión de proteasas en el microambiente tumoral. Esta revisión proporciona un panorama breve y actualizado sobre la participación de las proteasas en la progresión neoplásica.

Invasion and metastasis are the most important events in cancer progression. In these two phases, several molecules are implicated and have been long associated with several forms of cancer. Proteases play a critical role not only in tumor cell invasion, but also in the earliest stages of carcinogenesis and its associated changes: angiogenesis and metastasis. Aside from their ability to degrade the extracellular matrix, facilitate invasion and metastasis, proteases target a great variety of substrates that favor or inhibit cancer progression: b-FGF, HGF, VEGF, cell death receptors, cistatin-C, galectin, procollagen, and other proteases. Proteases are also signaling molecules that modulate other molecules by underlying pathways in addition to their degradative role. Proteases form interconnected cascades, circuits and networks that bring about the tumor's potential for malignancy. Although, proteases are regulated by diverse molecules, it is known that tumoral and stromal cells secrete several biological molecules, including cytokines and chemokines that directly or indirectly regulate the protease-expression within the tumor's microenvironment. The present review briefly summarizes some of the major aspects associated with the role of proteases in cancer progression.

Expression of Vascular Endothelial Growth Factor in Colorectal Cancer

PURPOSE: The neovascularization is an essential factor for the growth of solid organ cancer and especially vascular endothelial growth factor (VEGF) has been known to the very important mediator of neovascularization. Thus, this study was searching that expression of VEGF in colorectal cancer correlate to clinicopathologic factors. METHODS: We analyzed 93 patients with sporadic colorectal cancer who underwent colectomy and their specimens were studied immunohistochemistry at Chosun University hospital from March, 2002 to November, 2005. RESULTS: The expression rate of VEGF was 61 cases of all (65.6%). There were no significant relation VEGF expression to age, sex and lymph node metastasis. But, VEGF expression in colon cancer was 80.5% rather than 53.8% in rectal cancer (P=0.010). Correlation with T staging, expression of VEGF was 10.0% in pT0, 62.5% in pT1, pT2 and 77.2% in pT3, pT4 (P<0.0001), and correlation with TNM staging, expression of VEGF was 10.0% in stage 0, 63.2% in stage I, 72.0% in stage II, 73.3% in stage III and 100.0% in stage IV (P=0.001). CONCLUSIONS: Expression of VEGF in colorectal cancer closely correlates with cancer progression and VEGF was more expressed in colon cancer than rectum.

Comparison of p53 gene mutations in paired primary and metastatic gastric tumor tissues

Our previous study revealed that mutations of the p53 gene were detected by cDNA sequencing in one of four (25%) primary gastric tumors and in five of six (83%) gastric cancer cell lines. It was of interest that all five cell lines established from metastatic lesions had p53 gene mutations, while the single cell line established from a primary tumor lacked an abnormality. Thus, the current study was initiated to determine the frequency of p53 mutations in 10 pairs of samples from primary gastric carcinomas and their lymph node metastases, in addition to morphologically normal gastric mucosa. In addition, we correlated the findings with other relevant molecular markers including the metastasis associated nm23-H1 gene and loss of heterozygosity (LOH) using multiple polymorphic markers for chromosome 17p and sequencing the entire open reading frame (ORF) of the p53 gene. Five of ten (50%) patients were constitutionally heterozygous for one or more 17p and/or p53 probes (pYNZ 22, BamHI RFLP; pMct35.1, Mspl RFLP; php53cl, Bg/II RFLP), while none had LOH at the 17p and/or p53. A Bg/II RFLP for analysis of possible nm23-H1 somatic allelic deletion revealed no LOH out of four informative cases. One paired sample demonstrated the substitution of valine for isoleucine at codon 41 (GTT to ATT) in both primary gastric tumor and metastasis. Another metastatic sample demonstrated the substitution of proline for threonine at codon 278 (CCT to C/ACT) in addition to a non-mutated codon, while only the wild-type p53 sequence was present in the paired primary gastric tumor tissue.(ABSTRACT TRUNCATED AT 250 WORDS)