Long Yu

Nogo‐B is an important regulator of tumor angiogenesis. Expression of Nogo‐B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo‐B in liver cancer. In response to hypoxia, expression of Nogo‐B significantly increased in HCC tissues and cells. The distal hypoxia‐responsive element in the promoter was essential for transcriptional activation of Nogo‐B under hypoxic conditions, which is the specific site for hypoxia inducible factor‐1α (HIF‐1α) binding. In addition, Nogo‐B expression was associated with c‐Fos expression in HCC tissues. Nogo‐B expression was induced by c‐Fos, yet inhibited by a dominant negative mutant A‐Fos. Deletion and mutation analysis of the predicted activator protein‐1 binding sites revealed that functional element mediated the induction of Nogo‐B promoter activity, which was confirmed by ChIP. These results indicate that HIF‐1α and c‐Fos induce the expression of Nogo‐B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo‐B in tumor angiogenesis.

Suqin Shen, Huan Feng, Longjiang Liu, Wei Su, Long Yu & Jiaxue Wu. BMB Reports 2020;53:431-6. https://doi.org/10.5483/BMBRep.2020.53.8.008

Nuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.

Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti‐angiogenic therapeutic targets. We found that the expression level of Nogo‐B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo‐B depletion inhibited tumor angiogenesis, Nogo‐B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo‐B regulates tumor angiogenesis based on its association with integrin α_vβ₃ and activation of focal adhesion kinase. Moreover, Nogo‐B antibody successfully abolished the function of Nogo‐B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo‐B is an important tumor angiogenic factor and blocking Nogo‐B selectively inhibits tumor angiogenesis.

Multi-drug resistance (MDR) to anticancer drugs remains a major impediment in cancer therapy. A major goal for scientists is to identify more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects. Here, we reported that Pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, had potent anti-MDR activity. The average resistant fold (RF) of Z88 is 0.09 and 0.51 in KB/VCR (vincristine-resistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western Blot results showed that the expression levels of PARP, Bax, and Cyclin B1 all increased after treatment with 0.2 μmol/L (μM) of VCR combined with 10 μM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil-stimulated P- glycoprotein (P-gp) ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the RNA transcript level of ABCB1 and the protein expression level of P-gp. In conclusion, Z88 exerted potent anti-MDR activity in vitro and its mechanisms may be associated with dual-inhibition of the function and expression of P-gp. These findings encourage efforts todevelop more effective reversal agents to circumvent MDR.

Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis–trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC. These findings suggest that CyPJ may be a potential therapeutic target for HCC, and discovery of relevant inhibitors may facilitate development of a novel CyPJ-based targeting therapy. However, apart from the common inhibitor CsA, CyPJ has yet to be investigated as a target for cancer therapy. Here, we report structure-based identification of novel small molecule non-peptidic CyPJ inhibitors and their potential as antitumor lead compounds. Based on computer-aided virtual screening, in silico, and subsequently surface plasmon resonance analysis, 19 potential inhibitors of CyPJ were identified and selected for further evaluation of PPIase CyPJ inhibition in vitro. Thirteen out of 19 compounds exhibited notable inhibition against PPIase activity. Among them, the compound ZX-J-19, with a quinoxaline nucleus, showed potential for tumor inhibition; thus, we selected it for further structure–activity optimization. A total of 22 chemical derivatives with 2,3-substituted quinoxaline-6-amine modifications were designed and successfully synthesized. At least 2 out of the 22 derivatives, such as ZX-J-19j and ZX-J-19l, demonstrated remarkable inhibition of tumor cell growth, comparable to CsA but much stronger than 5-fluorouracil. These results indicate that these two small molecules represent novel potential lead compounds for CyPJ-based antitumor drug development.

This paper introduces part of the results of a research that was mainly focused in the area of south Shaanxi province of China. The main features of climate conditions in the researched region is introduced, based on which four main climate adaptive pattern languages implied in the traditional rural houses are identified, their applications in the contemporary rural houses are discussed. A summary of the research is provided and further researches are recommended.

To understand the relationship between the forms of buildings and their surrounding environment in the rural areas of west China, a series of literature reviews and field investigations were conducted targeting the self-designed and self-constructed rural houses in the Ningqiang county of south Shaanxi province. As a result, some typical forms of building clusters and individual buildings, which directly correspond with their specific environmental conditions, are identified in the researched region.

Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer. Prostate cancer is the leading cause of global cancer-related death. The development of improved diagnoses and novel therapies has been confounded by significant patient heterogeneity. During recent years, significant progress has been made in identifying the molecular alterations in prostate cancer using next-generation sequencing. SPOP gene was frequently altered by somatic point mutations in a distinct molecular subclass of prostate cancer, although the precise role that SPOP mutation plays in the development of prostate cancer is unclear. Mitochondria are highly motile organelles that undergo constant fission and fusion. Unbalanced mitochondrial fission and fusion events are associated with mitochondrial dysfunction and frequently linked to human cancer. Here, we are the first to report that SPOP mutations are associated with dysregulation of mitochondrial dynamics in prostate cancer and this finding may have potential clinical implications in prostate cancer treatment.