Prominent dermal accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection.

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin κ and λ light chains. The present case suggests that when inflammatory cell infiltration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection.

The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5.

BACKGROUND: The treatment of pancreatic cancer (PDAC) remains clinically challenging, and neoadjuvant therapy (NAT) offers down staging and improved surgical resectability. Abundant fibrous stroma is involved in malignant characteristic of PDAC. We aimed to investigate tissue remodelling, particularly the alteration of the collagen architecture of the PDAC microenvironment by NAT. METHODS: We analysed the alteration of collagen and gene expression profiles in PDAC tissues after NAT. Additionally, we examined the biological role of Ephrin-A5 using primary cultured cancer-associated fibroblasts (CAFs). RESULTS: The expression of type I, III, IV, and V collagen was reduced in PDAC tissues after effective NAT. The bioinformatics approach provided comprehensive insights into NAT-induced matrix remodelling, which showed Ephrin-A signalling as a likely pathway and Ephrin-A5 (encoded by EFNA5) as a crucial ligand. Effective NAT reduced the number of Ephrin-A5+ cells, which were mainly CAFs; this inversely correlated with the clinical tumour shrinkage rate. Experimental exposure to radiation and chemotherapeutic agents suppressed proliferation, EFNA5 expression, and collagen synthesis in CAFs. Forced EFNA5 expression altered CAF collagen gene profiles similar to those found in PDAC tissues after NAT. CONCLUSION: These results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.

Prevalence and Clinicopathologic Features of Intestinal Perforation Caused by Segmental Absence of the Intestinal Musculature in Adults.

Segmental absence of the intestinal musculature (SAIM) can cause intestinal perforation in adults. However, its prevalence and clinicopathologic features have not been well-described. This study aimed to determine the prevalence of SAIM-associated perforation and characterize its clinicopathologic features. We retrospectively examined 109 cases of intestinal perforation that underwent surgical resection from January 2009 to December 2019. SAIM was defined as the complete absence of the muscularis propria without extensive inflammation and fibrinous exudation around the perforation. SAIM was the second most frequent cause of perforation (26 cases: 24%), the most frequent cause being related to diverticulitis (39 cases: 36%). The most common site was the sigmoid colon (12 cases: 46.2%). The younger group (aged below 65 y) exhibited more frequent perforation of the upper segments of the gastrointestinal tract (from the duodenum to the descending colon) than the older group (65 y and above) (P=0.0018). No patients developed recurrence. The most common gross features were well-defined circular or small punched-out lesions, and the histologic features were complete absence of the muscularis propria and absence of hemorrhage and necrosis around the area of perforation. The characteristic features of SAIM were unique and their prevalence was higher than previously reported. The precise recognition of SAIM can aid in understanding the cause of perforation and avoiding further unnecessary examinations.

Molecular profiling of bone remodeling occurring in musculoskeletal tumors.

Musculoskeletal malignancy is often accompanied by aberrant bone remodeling, leading to tumor cell invasion into skeletal tissues and causing severe pain. BMPs, FGF-2, and RANKL have been identified as promising regulators in physiological bone remodeling. In this study, we explored the expressional profile of BMPs, FGF-2, and RANKL in 1361 patients with 22 varieties of musculoskeletal tumors. Notably, the expression of FGF-2 and RANKL was under detected in all patients. Among BMP1 to BMP15, we found that BMP1, BMP2, BMP4, BMP5, BMP6, and BMP7 were prevalent. In comparison with normal bones, osteosarcoma highly expressed BMP1, BMP2, BMP4, and BMP7 with statistical significance. Synovial sarcoma upregulated BMP4, BMP5, and BMP7; rhabdomyosarcoma increased BMP1 and BMP4; and alveolar soft part sarcoma upregulated BMP1, BMP4, and BMP7. To visualize the BMP-oriented interactions in a bone tumor microenvironment, we have developed novel software that analyzes numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome, delineating that osteosarcoma-secreted BMP-4 and synovial sarcoma-secreted BMP7 potently interact with osteoblasts, osteocytes, osteoclast precursors, and mature osteoclasts. Specifically, quantification analysis revealed that the relationship between osteosarcoma and mature osteoclast/precursor, BMP4-BMPR2 and BMP4-ACVR2A interactions were most potent. Regarding the association between osteosarcoma and osteocyte/osteoblast, BMP4-ACVR1 and BMP4-BMPR2 were the key interactions. In the connection between synovial sarcoma and mature osteoclast/precursor, BMP7-ACVR2A and BMP7-BMPR2 interactions were most remarkable. With regard to the cellular link between synovial sarcoma and osteocyte/osteoblast, BMP7-BMPR2 was identified as a potent interaction. In conclusion, our new outlook suggests delivering the pathological events that clinically underlie behind severe skeletal pain or fracture in musculoskeletal tumors.

Galectin-3: an immune checkpoint target for musculoskeletal tumor patients.

In the past decade, the development of immune checkpoint inhibitors in oncological clinical settings was in the forefront. However, the interest in musculoskeletal tumor patients as candidates for checkpoint inhibition remains underserved. Here, we are forwarding evidence proposing that galectin-3 (Gal-3) is an additional immune factor in the checkpoint processes. This review is the result of a large-scale cohort study depicting that overexpression of Gal-3 was widely prevalent in patients with musculoskeletal tumors, whereas T cell infiltrations were generally suppressed in the tumor microenvironment. Targeting Gal-3 would serve as a novel immune checkpoint inhibitor candidate in patients afflicted with aggressive musculoskeletal tumors.

Drug screening with a novel tumor-derived cell line identified alternative therapeutic options for patients with atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare intracranial tumor occurring predominantly in young children. The prognosis is poor, and no effective treatment is currently available. To develop novel effective therapies, there is a need for experimental models for AT/RT. In this research, we established a cell line from a patient's AT/RT tissue (designated ATRT_OCGH) and performed drug screening using 164 FDA-approved anti-cancer agents, to identify candidates for therapeutic options. We found that bortezomib, a proteasome inhibitor, was among the agents for which the cell line showed high sensitivity, along with tyrosine kinase inhibitors, topoisomerase inhibitors, and histone deacetylase inhibitors, which are known to exert anti-AT/RT effects. Concomitant use of panobinostat potentiated the inhibitory effect of bortezomib on AT/RT cell proliferation. Our findings may provide a rationale for considering combination therapy of panobinostat and bortezomib for treatment of AT/RT.

T-cell infiltration profile in musculoskeletal tumors.

Immunotherapy of musculoskeletal tumors remains clinically challenging and requires the development of gene-engineered/adoptive exogenous immune cells or the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Recently, endogenous B-cell infiltration into tumor microenvironments appears to be an essential promising prognostic factor controlling tumor progression in musculoskeletal malignancy. Here, we explored the level of T-cell infiltration by analyzing expression profiles of CD3E, CD4, and CD8A in 1366 patients and 23 histological types. The data revealed that CD3E and CD8A expressions were predominantly inhibited in bone tumors when compared with normal bone. CD4 expression was upregulated in limited types of tumors, including chondrosarcoma and giant cell tumor of bone, whereas other tumors demonstrated relatively lower expressions. Similarly, regarding soft tissue sarcoma, the expression of T-cell-related molecules was largely inhibited. Only in patients with rhabdomyosarcoma, CD3E and CD8A expressions were significantly upregulated, showing the nature of immune-active tumor. To visualize the immunological microenvironment of rhabdomyosarcoma, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome. It has led to the identification of molecular interactions between CD8+ T cell and rhabdomyosarcoma via Galectin3-LAG3 binding, which is a novel immune checkpoint recently identified. In conclusion, musculoskeletal tumors may be defined as immune-quiescent tumors, whereby targeting Galectin-3 and/or immune-infiltrative agents could be crucial in these immunologically noninflamed musculoskeletal tumors, accelerating immunotherapeutic response.

IAP inhibitor, Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity.

There is an increasing unmet need for successful immunotherapeutic interventions. Lymphocyte extravasation via tumor tissue endothelial cells (TECs) is required for lymphocyte infiltration into tumor sites. This study aimed to investigate the clinical significance of dysfunctional TECs in pancreatic ductal adenocarcinoma (PDAC) and identify chemical compounds that boost tumor-infiltrating lymphocyte (TIL) numbers. We performed immunohistochemical detection and clinicopathological analysis of VCAM-1 on TECs, which is essential for lymphocyte trafficking. We characterized the gene expression profiles of TECs from fresh PDAC tissues. We isolated compounds that upregulated VCAM-1 and E-selectin expression in TECs and examined their biological activities. Compared to endothelial cells from chronic pancreatitis tissue, TECs showed significantly lower VCAM-1 and E-selectin expression and significant weaknesses in lymphocyte adhesion and transmigration, resulting in decreased T cell infiltration around vessels. Patients with a relatively high percentage of VCAM-1+ vessels among all vessels in PDAC tissue had an improved prognosis. A bioinformatics survey demonstrated that TNFR1 signaling was involved in abnormal VCAM-1 and E-selectin expression in TECs. We screened compounds affecting TNFR1 signaling, and the IAP inhibitor, Embelin, induced these molecules on TECs and enhanced T cell adhesion to TECs and transmigration. Furthermore, in vivo, Embelin enhanced tumor-infiltrating T cell numbers, leading to an antitumor immune response. Embelin accelerates TIL infiltration and the antitumor immune response by recovering VCAM-1 expression in TECs. Our strategy may be a therapeutic approach for accelerating the immunotherapeutic response in immune-quiescent tumors, leading to clinical trials' success.

Autocrine motility factor and its receptor expression in musculoskeletal tumors.

Management of aggressive malignant musculoskeletal tumors is clinically challenging and awaits the identification of regulator(s) that can be therapeutically used to improve patient outcome. Autocrine motility factor (AMF), a secreted cytokine, is known to alter the bone microenvironment by linking to its receptor AMFR (AMF Receptor), leading to tumor progression. It was noted that both the ligand and its receptor belong to the moonlighting family of proteins, as they contribute to intracellular metabolic function such as glycolysis and gluconeogenesis by expressing glucose-6-phosphate isomerase AMF/GPI and higher protein degradation by expressing AMFR/gp78 functioning as ubiquitin ligase activity. Thus, AMF/GPI and AMFR/gp78 contribute to higher metabolic turnover of protein and glucose. Recently, a large-scale cohort study including 23 different histological types of musculoskeletal tumors revealed that patients with osteosarcoma, multiple myeloma, rhabdomyosarcoma, and angiosarcoma tend to express higher levels of AMF, whereas multiple myeloma patients expressed high levels of AMFR. Consistently, the cellular data showed that a variety of musculoskeletal tumors express AMF and components of bone microenvironment express AMFR. Thus, a novel outlook suggests a cellular link and cross-talk between musculoskeletal tumors and the skeletal milieu are regulated by AMF-AMFR signaling. This review will highlight the pharmacological need for AMF and AMFR inhibitors as unmet medical needs for patients with malignant musculoskeletal tumors.

Amplification of autocrine motility factor and its receptor in multiple myeloma and other musculoskeletal tumors.

Autocrine motility factor (AMF: GPI) and its receptor AMFR (AMF Receptor: gp78) regulate the metastatic process. Here, we have tested the expression levels of AMF, AMFR, and AMF × AMFR in 1348 patients with musculoskeletal tumor. The results depicted here identified that multiple myeloma highly express AMF × AMFR value as compared with normal bone samples (p < 0.00001). To visualize the AMF × AMFR autocrine amplification in multiple myeloma microenvironment, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, i.e., Environmentome. It has led to the identification that myeloma-associated interactions with normal bone cells including osteoblast, osteoclast, immunological components, and others in a paracrine manner. In conclusion, the data showed that AMF × AMFR amplification is a clinical manifestation in bone microenvironment of multiple myeloma.

Reduction of intrapancreatic neural density in cancer tissue predicts poorer outcome in pancreatic ductal carcinoma.

Neural invasion is one of the malignant features contributing to locally advanced and/or metastatic disease progression in patients with pancreatic ductal adenocarcinoma (PDAC). Few studies exist on the distribution and state of nerve fibers in PDAC tissue and their clinicopathological impacts. The aim of the present study was to investigate the clinicopathological characteristics and prognostic value of intrapancreatic neural alterations in patients with PDAC. We retrospectively analyzed 256 patients with PDAC who underwent macroscopic curative surgery. Nerve fibers, immunolabeled with a specific neural marker GAP-43, were digitally counted and compared among PDAC, chronic pancreatitis (CP) and normal pancreatic tissues. Interlobular nerve fibers were apparently hypertrophic in both CP and PDAC, although intrapancreatic neural density and nerve number decreased characteristically in PDAC. They tended to decrease toward the center of the tumor. Kaplan-Meier survival analyses revealed a statistically significant correlation between low neural density and shorter overall survival (OS) (P = 0.014), and between high neural invasion and shorter OS (P = 0.017). Neural density (P = 0.04; HR = 1.496; 95% CI 1.018-2.199) and neural invasion ratio (P = 0.064; HR = 1.439; 95% CI .980-2.114) were prognostic factors of shorter OS in the multivariate analysis. These findings suggest low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose a simple, practical and reproducible method (to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC), which has been validated using another cohort (n = 81).

Cancer Self-Defense: An Immune Stealth.

The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer-stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441-4. ©2017 AACR.

The influence of PSA autoantibodies in prostate cancer patients: a prospective clinical study-II.

The U.S. Preventive Services Task Force (USPSTF) has recommended against PSA-based screening for prostate cancer due to potential possibilities of false-results. Since no alternative test is available to replace it, we have initiated a trial with the purpose of establishing whether Galectin-3 (Gal-3) serum level and/or the patients' immune response to PSA and Gal-3 antigens could complement the PSA test as diagnostic tools for prostate cancer patients. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were recruited and classified into 5 different groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). The primary endpoints were the levels of serum PSA, PSA autoantibodies (AAPSA), Gal-3, and Gal-3 autoantibodies (AAGal-3). Data were analyzed by Spearman's rank correlation (rho) and least squares linear regression modeling. The expression levels of PSA, AAPSA, Gal-3, and AAGal-3 were determined in both healthy controls and prostate cancer patients. Negative correlations were observed between PSA and AAPSA levels among all 95 men combined (rho = -0.321, P = 0.0021; fitted slope -0.288, P = 0.0048), and in metastatic patients (rho = -0.472, P = 0.0413; fitted slope -1.145, P = 0.0061). We suggest an association between PSA and AAPSA, whereby the AAPSA may alter PSA levels. It provides a novel outlook for prostate cancer diagnosis, and should serve as a basis for an all-inclusive diagnostic trial centering on patients with metastasis.

Positive associations between galectin-3 and PSA levels in prostate cancer patients: a prospective clinical study-I.

Galectin-3 (Gal-3), an oncogenic pro-inflammatory protein, has been suggested as a possible complementary diagnostic candidate to prostate specific antigen (PSA) blood test for prostate cancer patients. The presence of the proteins in the circulation (biomarkers) may elicit an intrinsic humoral immune reaction by generating autoantibodies, which consequently could alter the detection levels. Here, we report the associations of the two prostate cancer biomarkers, Gal-3 and PSA in patients at different clinical states of prostate cancer while taking into account the autoantibody levels. A blind, prospective, single institution, pilot study was conducted. A total of 95 men were classified into 5 groups: healthy controls (Group1), newly diagnosed patients (Group2), no recurrence after local therapy (Group3), rising PSA after local therapy (Group4), and metastatic patients (Group5). Gal-3 and PSA level were divided by their respective autoantibodies, which yielded relative PSA and relative Gal-3 levels. After the adjustments, Spearman's rank correlations and linear regression modeling revealed the positive associations between relative Gal-3 and relative PSA levels among all 95 men combined (rho = 0.446, P < 0.0001; fitted slope 0.448, P < 0.0001), in Group2 (rho = 0.616, P = 0.0050; fitted slope 0.438, P =0.0011), and Group3 (rho = 0.484, P = 0.0360; fitted slope 0.470, P = 0.0187). The data show positive associations of relative Gal-3 and relative PSA levels in prostate cancer patients, notably at early clinical time course. Allowing for the influence of autoantibodies, Gal-3 level might be considered as a potential biomarker since it is positively associated with PSA level.

Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management.

The skeleton is frequently a secondary growth site of disseminated cancers, often leading to painful and devastating clinical outcomes. Metastatic cancer distorts bone marrow homeostasis through tumor-derived factors, which shapes different bone tumor microenvironments depending on the tumor cells' origin. Here, we propose a novel insight on tumor-secreted Galectin-3 (Gal-3) that controls the induction of an inflammatory cascade, differentiation of osteoblasts, osteoclasts, and bone marrow cells, resulting in bone destruction and therapeutic failure. In the approaching era of personalized medicine, the current treatment modalities targeting bone metastatic environments are provided to the patient with limited consideration of the cancer cells' origin. Our new outlook suggests delivering individual tumor microenvironment treatments based on the expression level/activity/functionality of tumor-derived factors, rather than utilizing a commonly shared therapeutic umbrella. The notion of "Gal-3-associated bone remodeling" could be the first step toward a specific personalized therapy for each cancer type generating a different bone niche in patients afflicted with non-curable bone metastasis.

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158-175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.

Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.

Galectin-3 (Gal-3, LGALS3) is a pleotropic versatile, 29-35 kDa chimeric gene product, and involved in diverse physiological and pathological processes, including cell growth, homeostasis, apoptosis, pre-mRNA splicing, cell-cell and cell-matrix adhesion, cellular polarity, motility, adhesion, activation, differentiation, transformation, signaling, regulation of innate/adaptive immunity, and angiogenesis. In multiple diseases, it was found that the level of circulating Gal-3 is markedly elevated, suggesting that Gal-3-dependent function is mediated by specific interaction with yet an unknown ubiquitous cell-surface protein. Recently, we showed that Gal-3 attenuated drug-induced apoptosis, which is one of the mechanisms underlying multidrug resistance (MDR). Here, we document that MDR could be mediated by Gal-3 interaction with the house-keeping gene product e.g., Na+/K+-ATPase, and P-glycoprotein (P-gp). Gal-3 interacts with Na+/K+-ATPase and induces the phosphorylation of P-gp. We also find that Gal-3 binds P-gp and enhances its ATPase activity. Furthermore Gal-3 antagonist suppresses this interaction and results in a decrease of the phosphorylation and the ATPase activity of P-gp, leading to an increased sensitivity to doxorubicin-mediated cell death. Taken together, these findings may explain the reported roles of Gal-3 in diverse diseases and suggest that a combined therapy of inhibitors of Na+/K+-ATPase and Gal-3, and a disease specific drug(s) might be superior to a single therapeutic modality.

Gp78, an E3 ubiquitin ligase acts as a gatekeeper suppressing nonalcoholic steatohepatitis (NASH) and liver cancer.

Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78-/- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors. Acute ER stress revealed that loss of gp78 results in up regulation of unfolded protein response (UPR) pathways and SREBP-1 regulating de novo lipogenesis, responsible for fatty liver. Tissue array of human hepatocellular carcinoma (HCC) demonstrated that the expression of gp78 was inversely correlated with clinical grades of cancer. Here, we have described the generation of the first preclinical experimental model system which spontaneously develops age-related NASH and HCC, linking ERAD to hepatosteatosis, cirrhosis, and cancer. It suggests that gp78 is a regulator of normal liver homeostasis and a tumor suppressor in human liver.