PKB/Akt-dependent regulation of inflammation in cancer

Chronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development

Integrated Akt/PKB Signaling in Immunomodulation and Its Potential Role in Cancer Immunotherapy

T cell development and maturation involve a variety of defined and coordinated developmental stages under the control of a variety of signaling networks. They function as the major mediator in cell-based immunity that defends against pathogen infections and executes immune surveillance against tumor cells. Protein kinase B (PKB, also called Akt) is central to multiple signaling pathways and transduces extracellular signals to dictate cellular responses towards proliferation, migration, anti-apoptosis, and maintenance of metabolic homeostasis. Although the prosurvival function of PKB was thought to be responsible for most of the functions regulated by PKB, emerging evidence has started to dissect its role in immunomodulation. More importantly, hyperactivation of PKB in cancer stroma frequently occurs in patients treated clinically with targeted cancer therapies, where it acts as a key mediator involved in the trapping of host immune cells in the vicinity of tumors, which supports cancer cell invasion and the escape of cancer cells from host immune surveillance. Encouragingly, recent studies have shown that inhibition of PKB improves the recognition of cancer cells by the host immune system, indicating a potential clinical strategy to rekindle the suppressed host immune response through the specific targeting of PKB. In this review, we explore how PKB signaling contributes to T cell development and cellular immune responses and discuss the mechanistic roles that PKB plays in the creation of immunosuppressive conditions and the escaping of immune recognition in the microenvironment of cance

USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients

LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy

Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo-Independent Regulation of Heat Shock Protein 70 Family Members.

Transcriptional enhancer factor domain family member 4 (TEAD4) is a downstream effector of the conserved Hippo signaling pathway, regulating the expression of genes involved in cell proliferation and differentiation. It is up-regulated in several cancer types and is associated with metastasis and poor prognosis. However, its role in hepatocellular carcinoma (HCC) remains largely unexplored. Using data from The Cancer Genome Atlas, we found that TEAD4 was overexpressed in HCC and was associated with aggressive HCC features and worse outcome. Overexpression of TEAD4 significantly increased proliferation and migration rates in HCC cells in vitro as well as tumor growth in vivo. Additionally, RNA sequencing analysis of TEAD4-overexpressing HCC cells demonstrated that TEAD4 overexpression was associated with the up-regulation of genes involved in epithelial-to-mesenchymal transition, proliferation, and protein-folding pathways. Among the most up-regulated genes following TEAD4 overexpression were the 70-kDa heat shock protein (HSP70) family members HSPA6 and HSPA1A. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction experiments demonstrated that TEAD4 regulates HSPA6 and HSPA1A expression by directly binding to their promoter and enhancer regions. The pharmacologic inhibition of HSP70 expression in TEAD4-overexpressing cells reduced the effect of TEAD4 on cell proliferation. Finally, by overexpressing TEAD4 in yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ)-knockdown HCC cells, we showed that the effect of TEAD4 on cell proliferation and its regulation of HSP70 expression does not require YAP and TAZ, the main effectors of the Hippo signaling pathway. Conclusion: A novel Hippo-independent mechanism for TEAD4 promotes cell proliferation and tumor growth in HCC by directly regulating HSP70 family members

Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma

Protein kinases are critical players of signal transduction pathways involved in development, physiological and pathological processes. Deregulation of protein kinase signaling is found to be causal or related to varieties of human diseases, such as cancer, cardiovascular disease and diabetes. The human genome encodes 518 protein kinases. Approximately 60 out of them belong to the AGC group of Serine/Threonine protein kinases, including the ste20 like MST kinase family and NDR kinase family. Members of these families are highly conserved from yeast to men and regulate essential processes such as growth, proliferation and apoptosis. The Hippo pathway is a recently identified tumor suppressive network, where the MST-NDR family kinases form a kinase cascade regulating the downstream signaling through the effector YAP/TAZ. In addition to signaling through the NDR family kinases, the Hippo/MST kinases also control cell apoptosis bypass these classical effectors YAP/TAZ. Despite the fact that JNK, FOXO3, H2B are well characterized downstream targets of apoptotic MST kinases, the regulatory mechanisms of apoptotic MST signaling are still largely unknown. The human MOB family consists of six members encoded by six different genes (hMOB1A, -1B, -2, -3A, -3B and -3C). While as an activator for hMOB1A/B in MST-LATS/NDR kinase cascade, hMOB2 is a specific negative regulator of NDR kinase by competing the binding of hMOB1 to NDR kinase. Although hMOB3 family members share higher amino acid identity with hMOB1 than hMOB2, hMOB3 proteins do not interact or (de)activate NDR family kinases. Hence, the functions of hMOB3A/B/C are completely undefined. A previous microarray study performed in the lab indicated that hMOB3 family members were deregulated in glioblastoma. In the present study, we first investigated the pathological roles of human MOB3 proteins and found that hMOB3 is highly upregulated in glioblastoma. Moreover, mRNA expression levels of hMOB3 members correlate with survival, suggesting hMOB3 members as potential prognostic markers. We extended the biochemical analysis by looking for the interaction partners of hMOB3 and demonstrated that hMOB3 binds to MST1 and inhibits the apoptotic cleavage of MST1 kinase. We further verified that hMOB3 promotes tumorigenesis of gliobalstoma cells in vivo by a U87MG derived flank model. Taken together, our results suggest that manipulate hMOB3 might represent a therapeutic strategy in malignant gliomas

LATS1-Beclin1 mediates a non-canonical connection between the Hippo pathway and autophagy

Understanding the mechanisms of evasive resistance in cancer is of great importance to develop efficient therapies. Analyzing the molecular mechanisms underlying therapy resistance of hepatocellular carcinoma (HCC), we have discovered a kinase-activity independent role of LATS1 (large tumor suppressor) but not LATS2 in regulating sorafenib-induced lethal autophagy in HCC. We have found that the autophagy regulatory role of LATS1 is a general phenomenon in response to various stimuli of autophagy induction which relies on a LATS1-specific protein domain. Mechanistically, the autophagy regulatory role of LATS1 is coupled with Beclin-1 (BECN1) K27-linked ubiquitination and BECN1 self-dimerization. Our study highlights a LATS1-mediated non-classical interaction between the Hippo signaling pathway and autophagy in therapy response and carcinogenesis

Clinical Analysis of Castleman’s Disease of the Lacrimal Gland

Objective. To explore the clinical manifestations, imaging characteristics, and pathological characteristics of Castleman’s disease of the lacrimal gland, enhance the knowledge of the disease, and improve the level of its diagnosis and treatment. Methods. In the retrospective study, the data of 5 patients diagnosed with Castleman’s disease of the lacrimal gland in Tianjin Medical University Eye Hospital from 2014 to 2018 were analyzed, and the relevant literature was reviewed. Results. All the 5 patients were confirmed by pathological examination. Clinical manifestations were characterized by mass occupying lesions in the lacrimal gland area, without obvious pain, accompanied by eyelid swelling and ptosis, as well as space-occupying symptoms. Imaging examination showed that there was a soft tissue mass in the enlarged lacrimal gland area, and the mass was rich in blood flows while showing no obvious specificity, which could invade the surrounding muscles. All patients underwent surgical resection. Pathological results showed that 1 case was of the hyaline-vascular type, 3 cases were of the plasma cell type, and 1 case showed malignant transformation to plasma cell tumor. Conclusion. Castleman’s disease of the lacrimal gland is a rare orbital lymphoproliferative disease lacking specificity in clinical manifestations and imaging examination. As there are difficulties in differentiating the disease from orbital inflammatory pseudotumor and orbital lymphoma, its diagnosis still depends on pathological examination. The disease is mainly treated with surgical resection, and the pathological type is determined postoperatively

Ectopic orbital meningioma: a retrospective case series

Abstract Background To evaluate the ophthalmic manifestations and radiographic features of ectopic orbital meningioma to improve diagnostic accuracy. Methods Patient data from patients admitted to our institution during a 217-month period from August 1999 to September 2017 were included. Patient ophthalmic manifestations, radiographic features (CT and MRI), diagnosis, pathology, therapeutic regimens, and prognosis were retrospectively reviewed. Results Six patients with ectopic orbital meningioma were identified. The mean age at the first visit was 33.2 years (range, 7–56 years). All six patients displayed manifestations of exophthalmos, upper eyelid oedema, and motility impairment with a mean history of illness of 20.3 months (range 3–72 months). Optical lesions were located in the superonasal extraconal compartment (3/6, 50%), bitemporal extraconal compartment (1/6, 16.7%) and orbital intraconal compartment (2/6, 33%). Radiographic features were ill-defined, heterogeneous, enhancing soft tissue masses with extraocular muscular adhesion (6/6, 100%) and calcification (1/6, 16.7%), not adjacent to the optic nerve and not extending along the dura. Six cases were treated intraoperatively with complete surgical resection, indicating that all lesions were independent of the optic nerve and sphenoid ridge. The histopathologic classification was mostly of meningothelial cells (5/6, 83%). Immunohistochemistry revealed EMA and vimentin to have positive expression in all six cases, while two cases were calponin-positive and strongly expressed in the olfactory bulb. Postoperatively, lesions caused no visual impairment, and there were no cases of recurrence. Conclusions Ectopic orbital meningiomas are rare tumours that are not easily diagnosed without postoperative histopathology. This report highlights some of the distinguishing features of isolated orbital lesions, especially around the location of frontoethmoidal suture. Accompanying upper eyelid oedema and eye mobility restriction were observed to be dissimilar to other orbital tumours. In these cases, a diagnosis of ectopic orbital meningioma should be considered