A key driver to promote HCC: Cellular crosstalk in tumor microenvironment.

Liver cancer is the third greatest cause of cancer-related mortality, which of the major pathological type is hepatocellular carcinoma (HCC) accounting for more than 90%. HCC is characterized by high mortality and is predisposed to metastasis and relapse, leading to a low five-year survival rate and poor clinical prognosis. Numerous crosstalk among tumor parenchymal cells, anti-tumor cells, stroma cells, and immunosuppressive cells contributes to the immunosuppressive tumor microenvironment (TME), in which the function and frequency of anti-tumor cells are reduced with that of associated pro-tumor cells increasing, accordingly resulting in tumor malignant progression. Indeed, sorting out and understanding the signaling pathways and molecular mechanisms of cellular crosstalk in TME is crucial to discover more key targets and specific biomarkers, so that develop more efficient methods for early diagnosis and individualized treatment of liver cancer. This piece of writing offers insight into the recent advances in HCC-TME and reviews various mechanisms that promote HCC malignant progression from the perspective of mutual crosstalk among different types of cells in TME, aiming to assist in identifying the possible research directions and methods in the future for discovering new targets that could prevent HCC malignant progression.

Tumor-promoting properties of karyopherin ß1 in melanoma by stabilizing Ras-GTPase-activating protein SH3 domain-binding protein 1.

The nuclear import receptor karyopherin ß1 (KPNB1), a member of the Karyopherin protein family, is reported to be overexpressed in various cancers and promote carcinogenesis. By analyzing the correlation between the expression of KPNB1 and the overall survival rate of melanoma patients, we found that melanoma patients with higher expression of KPNB1 had worse survival. Furthermore, the database analyzed that the KPNB1 mRNA level was higher in melanoma samples than that in skin nevus tissues. We thus proposed that KPNB1 played a role in promoting melanoma development, and conducted gain-of- and loss-of-function experiments to test our hypothesis. We found that KPNB1 knockdown significantly retarded the growth and metastasis of melanoma cells in vitro and in vivo, and increased their sensitivity towards the anti-tumor drug cisplatin. KPNB1 overexpression had opposite effects. Notably, in melanoma cells, KPNB1 overexpression significantly decreased Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) protein level, which was also overexpressed in melanoma samples and enhanced malignant behaviors of melanoma cells. We further demonstrated that KPNB1 overexpression induced deubiquitination of G3BP1, and prevented its degradation. However, KPNB1 overexpression hardly affected the nuclear translocation of G3BP1. Additionally, alterations induced by KPNB1 overexpression were partly reversed by G3BP1 inhibition. Therefore, the results suggest that KPNB1 may promote melanoma progression by stabilizing the G3BP1 protein. KPNB1-G3BP1 axis represents a potential therapeutic targetable node for melanoma.

Mdivi-1 alleviates atopic dermatitis through the inhibition of NLRP3 inflammasome.

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin-related protein 1 (Drp1)-dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1 has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi-1 on experimental AD. We firstly detected the effects of mdivi-1 on primary human keratinocytes in an inflammatory cocktail-induced AD-related inflammation in vitro. Results showed that mdivi-1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase-1, GSDMD-NT, mature interleukin (IL)-1ß and IL-18 in keratinocytes under AD-like inflammation. Next, mouse model of AD-like skin lesions was induced by epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) and mdivi-1 (25 mg/kg/day, days 5-33 during construction of AD model) was intraperitoneally injected into DNCB-induced mice. AD mice with mdivi-1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL-4, IL-5 and IL-13 in the lesional tissues. Indeed, mdivi-1 significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB-treated skin tissues. Mechanically, mdivi-1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF-κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi-1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi-1 might exert this function by inhibiting mitochondrial fission and subsequently blocking NF-κB pathway.

Anti-IL-33 Antibody Has a Therapeutic Effect in an Atopic Dermatitis Murine Model Induced by 2, 4-Dinitrochlorobenzene.

IL-33 is a new member of the IL-1 family that plays a role in allergic disease. In this study, we evaluated the potential on the inhibition of atopic dermatitis (AD) of anti-mouse IL-33 antibody (αIL-33Ab) using 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice model. We treated mice with αIL-33Ab via subcutaneous injection of each DNCB treatment 1 h later from day 1 to day 33 for 14 times. A control group received tacrolimus. Skin lesion and scratching behavior were compared. Ear thickness, dermatitis score, eosinophils and mast cells infiltration, and serum IgE levels were also analyzed. Correlations between serum IL-33 as well as soluble(s) ST2 and AD disease activity index in human AD were also investigated. DNCB-induced AD-like mice treated with αIL-33Ab showed improved AD-like symptoms. Eosinophils and mast cells infiltration and serum IgE levels were also significantly reduced by αIL-33Ab. Our study suggests that blockade of IL-33 has a curative effect on AD.

[Effects of stromal cells derived from the normal prostate on the glycolysis of prostate cancer cells].

OBJECTIVE: To investigate the effects of prostate stromal cells from different zones of normal prostate tissue on the growth of prostate cancer cells and their action mechanisms. METHODS: We extracted stromal cells in the fresh normal prostatic tissue derived from the peripheral zone (PZ) or transitional zone (TZ), amplified them in vitro, and used the supernatants of the cells as conditioned media to culture hormone-resistant prostate cancer DU145 cells. We measured the growth curve of the tumor cells using the CCK8 method, determined the number and viability of the cells by trypan blue staining, evaluated their invasiveness by scratch test, and detected the effects of the stromal cells on the key enzymes in the glycolysis of the tumor cells by Western blot. RESULTS: The conditioned medium with the PZ-derived stromal cells promoted, while that with the TZ-derived stromal cells inhibited the growth of the tumor cells. The former significantly increased, while the latter markedly decreased the expressions of the key enzymes hexokinase 2 (HK-2), pyruvate kinase 2 (PKM-2), lactate dehydrogenase (LDHA), and pyruvate dehydrogenase (PDH) in the glycolysis of the tumor cells. CONCLUSION: Prostate stromal cells from different zones exert different influences on the growth of tumor cells, which may be associated with their different effects on the glycolysis of tumor cells.

Normal peripheral prostate stromal cells stimulate prostate cancer development: roles of c-kit signal.

BACKGROUND: To investigated the peripheral stromal cell conditioned medium (CM) -stimulated c-kit-JAK2-STAT1 pathway in prostate cancer. METHODS: CM harvested from normal prostate peripheral stromal cells was added to DU145 cells. DU145 cell viability and migration were measured by cell counting kit-8 reagent and Transwell analysis respectively. Colony and sphere formation efficiencies of DU145 cells co-cultured with CM from human prostate stromal cells were also measured. DU145cells were stably transfected with lentivirus-mediated shRNA for c-kit silencing. RESULTS: C-kit expression in prostate cancer was found to be significantly higher than in benign prostatic hyperplasia and positively associated with Gleason scores. The growth, migration and capacity of clonogenic property of DU145 cells significantly increased upon exposure to peripheral stromal CM and then were inhibited after silencing the expression of c-kit. The levels of c-kit, pJAK2 and pSTAT1 were significantly induced by peripheral zone stromal CM compared with controls in serum free medium and the levels of pJAK2 and pSTAT1 decreased after c-kit silencing. CONCLUSIONS: C-kit hyper-expression promotes the development of prostate cancer. The peripheral stromal cell CM stimulated c-kit-JAK2-STAT1 pathway in prostate cancer cell viability, migration, and capacity of clonogenic property. This may lead to a greater understanding of the role of c-kit in prostate cancer and provide a potential therapeutic target for prostate cancer.