The unexpected and unresolved roles of PDGFRA and PDGFRB in T-cell acute lymphoblastic leukemia.

Not available.

ARHGAP15 promotes metastatic colonization in gastric cancer by suppressing RAC1-ROS pathway.

The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.

Targeting TROY-mediated P85a/AKT/TBX3 signaling attenuates tumor stemness and elevates treatment response in hepatocellular carcinoma.

BACKGROUND: Previous in vitro hepatocyte differentiation model showed that TROY was specifically expressed in liver progenitor cells and a small proportion of hepatocellular carcinoma cells, suggesting that TROY may participate in hepatocellular carcinoma (HCC) stemness regulation. Here, we aim to investigate the role and mechanism of TROY in HCC pathogenesis. METHOD: Bioinformatics analysis of the TCGA dataset has been used to identify the function and mechanism of TROY. Spheroid, apoptosis, and ALDH assay were performed to evaluate the stemness functions. Validation of the downstream pathway was based on Western blot, co-immunoprecipitation, and double immunofluorescence. RESULTS: HCC tissue microarray study found that a high frequency of TROY-positive cells was detected in 53/130 (40.8%) of HCC cases, which was significantly associated with poor prognosis and tumor metastasis. Functional studies revealed that TROY could promote self-renewal, drug resistance, tumorigenicity, and metastasis of HCC cells. Mechanism study found that TROY could interact with PI3K subunit p85α, inducing its polyubiquitylation and degradation. The degradation of p85α subsequently activate PI3K/AKT/TBX3 signaling and upregulated pluripotent genes expression including SOX2, NANOG, and OCT4, and promoted EMT in HCC cells. Interestingly, immune cell infiltration analysis found that upregulation of TROY in HCC tissues was induced by TGF-ß1 secreted from CAFs. PI3K inhibitor wortmannin could effectively impair tumor stemness to sorafenib. CONCLUSION: We demonstrated that TROY is an HCC CSC marker and plays an important role in HCC stemness regulation. Targeting TROY-positive CSCs with PI3K inhibitor wortmannin combined with chemo- or targeted drugs might be a novel therapeutic strategy for HCC patients.

ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly.

The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient, which serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that calcium release-activated calcium modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, predominantly upregulated in the lymph node metastasis of gastric cancer, supports cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in gastric cancer tissues significantly correlated with poor differentiation, invasion, lymph node metastasis, and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation, and metastasis in both gastric cancer cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of gastric cancer cells by inducing FAK-mediated MAPK/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of gastric cancer. SIGNIFICANCE: These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway.

The BMP antagonist, SOSTDC1, restrains gastric cancer progression via inactivation of c-Jun signaling.

Gastric cancer is commonly diagnosed at an advanced stage when metastasis is almost inevitable. Despite numerous novel regulators have been identified in driving gastric cancer progression, much remains unclear due to the complex nature of cancer. Comparison of the transcriptome profiles of gastric primary tumor tissue, with its matched non-tumor and lymph node metastasis revealed frequent stepwise down-regulation of sclerostin domain containing 1 (SOSTDC1) related with tumor progression. Clinically, deficiency of this gene is associated with shortened survival of patients. Our results suggest that SOSTDC1 confers tumor-suppressive features in gastric cancer and silencing of it accelerates tumor growth and promotes the formation of lung metastasis. Although SOSTDC1 displayed limited inhibition of canonical SMAD-dependent bone morphogenetic proteins (BMP) pathway, it remarkably restrained the c-Jun activation and transcription of c-Jun downstream targets in the noncanonical BMP signaling pathway. Furthermore, c-Jun N-terminal kinase (JNK) blockage attenuated cell proliferative and migrative advantages of SOSTDC1 knockdown cell lines. Our study comprehensively elucidated the role of SOSTDC1 in gastric cancer progression and the results translate into potential therapy for gastric cancer.

Gold(i) phosphine compounds as parasite attenuating agents for malaria vaccine and drug development.

Here, the anti-malarial activity of two gold(i) phosphine compounds auranofin and [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with [Au(d2pype)2]Cl (1 or 2 µM) or auranofin (2 µM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days post inoculation. In some experiments, there was microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type P. chabaudi AS. In experiments where microscopically detectable parasites were observed following in vivo inoculation, mice were subsequently fully protected against a challenge infection with wildtype parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit P. chabaudi AS growth in vivo when administered orally. Gold compounds act via the inhibition of antioxidant systems which are critical in the pathogen's survival from attack by the host oxidants. In vitro, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand, in vivo, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of P. falciparum and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.

The cylindromatosis (CYLD) gene and head and neck tumorigenesis.

Germline CYLD mutation is associated with the development of a rare inheritable syndrome, called the CYLD cutaneous syndrome. Patients with this syndrome are distinctly presented with multiple tumors in the head and neck region, which can grow in size and number over time. Some of these benign head and neck tumors can turn into malignancies in some individuals. CYLD has been identified to be the only tumor suppressor gene reported to be associated with this syndrome thus far. Here, we summarize all reported CYLD germline mutations associated with this syndrome, as well as the reported paired somatic CYLD mutations of the developed tumors. Interestingly, whole-exome sequencing (WES) studies of multiple cancer types also revealed CYLD mutations in many human malignancies, including head and neck cancers and several epithelial cancers. Currently, the role of CYLD mutations in head and neck carcinogenesis and other cancers is poorly defined. We hope that this timely review of recent findings on CYLD genetics and animal models for oncogenesis can provide important insights into the mechanism of head and neck tumorigenesis.

A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy.

The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for "ALK-rearranged" lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.