A Barth Syndrome Patient-Derived Point Mutation in Drives Progressive Cardiomyopathy in Mice.

Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored knock-in mouse allele () that phenocopies BTHS clinical traits.

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia.

Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis , the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood.

SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA-deficient cells.

The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here, we performed a kinome-wide synthetic lethality screen in FANCA fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells.

Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma.

Background: Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases developed from trophoblasts. ASPP (Ankyrin-repeat, SH3-domain and proline-rich region containing protein) family proteins, ASPP1 and ASPP2, have been reported to be dysregulated in GTD. They modulate p53 activities and are responsible for multiple cellular processes.

Impact of iASPP on chemoresistance through PLK1 and autophagy in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival.

Identification of nonsynonymous TP53 mutations in hydatidiform moles.

Hydatidiform mole (HM), an unusual pregnancy with pure or predominant paternal genetic contribution, is the most common form of gestational trophoblastic disease. Most HM regress after uterine evacuation but some will develop into persistent disease or even frank malignancy. Although p53 is highly expressed in HM, TP53 mutations have rarely been detected in previous studies.

Erythropoietin drives breast cancer progression by activation of its receptor EPOR.

Breast cancer is a leading cause of cancer-related deaths. Anemia is common in breast cancer patients and can be treated with blood transfusions or with recombinant erythropoietin (EPO) to stimulate red blood cell production. Clinical studies have indicated decreased survival in some groups of cancer patients treated with EPO.

Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.

It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival.Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion.

FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo.

Protein deregulation associated with breast cancer metastasis.

Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events.

RanGTPase: a candidate for Myc-mediated cancer progression.

Background: Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown.

Methods: We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively.

Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells.

Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms.

Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression.

Emerging evidence has indicated a role of the bone morphogenetic proteins (BMP) in the pathogenesis of certain cancers. The signaling of BMP family members is tightly regulated by their antagonists, including noggin and SOST, which are, in turn, positively regulated by BMP, thereby forming a negative feedback loop. Consequently, the expression of these antagonists should be taken into account in studies on the prognostic significance of BMP.

Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways.

Purpose: Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities.

Experimental Design: Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran.

The role of Pea3 group transcription factors in esophageal squamous cell carcinoma.

The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium.

Interleukin-2 induces NF-kappaB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells.

Deregulation of nuclear factor (NF)-kappaB signalling is common in cancers and is essential for tumourigenesis. Constitutive NF-kappaB activation in extranodal natural killer (NK)-cell lymphoma, nasal type (ENKL) is known to be associated with aberrant nuclear translocation of BCL10. Here we investigated the mechanisms leading to NF-kappaB activation and BCL10 nuclear localization in ENKLs.

CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation.

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHSmu were detected in follicular lymphomas and exclusively in germinal center B cell-ike (GCB)-DLBCLs. CD44 is not expressed in reactive GC B cells.

Stephania tetrandra prevents and regresses liver fibrosis induced by carbon tetrachloride in rats.

Background And Aim: There is currently no safe and effective treatment for liver fibrosis. We have previously shown that Stephania tetrandra (ST) and Salvia miltiorrhiza (SM) suppress cell proliferation and enhance apoptosis of hepatic stellate cell (HSC) in vitro. In this study, we aimed to investigate the anti-fibrotic effect of these two herbs in vivo.

TWIST modulates prostate cancer cell-mediated bone cell activity and is upregulated by osteogenic induction.

TWIST, a helix-loop-helix transcription factor, is highly expressed in many types of human cancer. We have previously found that TWIST confers prostate cancer cells with an enhanced metastatic potential through promoting epithelial-mesenchymal transition (EMT) and a high TWIST expression in human prostate cancer is associated with an increased metastatic potential. The predilection of prostate cancer cells to metastasize to bone may be due to two interplaying mechanisms (i) by increasing the rate of bone remodeling and (ii) by undergoing osteomimicry.

Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis.

Background: The antiapoptotic and epithelial-mesenchymal transition activities of Twist have been implicated in the neoplastic transformation and the development of metastasis, respectively. Upregulation of Twist, described in several types of human cancer, also acts as a prognostic marker of poor outcome.

Aim: To investigate Twist expression in oesophageal squamous cell carcinoma (SCC) and its prognostic value in a Chinese cohort of patients with oesophageal SCC.

Effect of celecoxib on experimental liver fibrosis in rat.

Background/aim: Cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes prostaglandin synthesis, has been implicated in a number of hepatic stellate cell (HSC) functions. In the current study, we assessed the in vivo effect of celecoxib, a COX-2-selective inhibitor, in experimental liver fibrosis in rats.

Methods: Male Sprague-Dawley rats received experimental treatments for 5 weeks.

Inhibition of gastric cancer-associated angiogenesis by antisense COX-2 transfectants.

We characterized the effects of selective Cox-2 inhibition on the angiogenesis gastric cancer cell line SGC7901 by stable transfection of antisense Cox-2 cDNA (Cox-2-AS) or pharmacological inhibition by selective cox-2 inhibitor (NS398). The conditioned media obtained from SGC7901 treated with Cox-2-AS or NS398 suppressed the proliferation, migration and tube formation of human umbilical vein endothelial cells. Moreover, both treatments inhibited in vivo angiogenesis.

Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma.

Although gastric cancer with cyclooxygenase (COX)-2 overexpression is associated with poor prognosis, the mechanistic pathway remains unknown. We examined the associations between expressions of COX-2 and vascular endothelial growth factor (VEGF) in both gastric cancer cells and in human gastric cancer. The gastric cell line, Kato III, was transiently transfected with cox-2 expressing vector.

Inactivation of helicase-like transcription factor by promoter hypermethylation in human gastric cancer.

Helicase-like transcription factor (HLTF), a member of the SWI/SNF (mating type switching/sucrose nonfermenting) chromatin-remodeling complex, is recently found to be inactivated by promoter hypermethylation in human colorectal cancer. However, the role of this putative tumor suppressor gene in other tumors has not been determined. We evaluated the role of HLTF promoter hypermethylation in gastric cancer.