Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

LHPP suppresses proliferation, migration, and invasion in hepatocellular carcinoma and pancreatic cancer by inhibiting EGFR signaling pathway.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been reported to be a new tumor suppressor with a significant inhibitory effect in various cancers. Although LHPP has been repeatedly shown to inhibit the progression of various tumors by inhibiting the phosphorylation of AKT, up to now, the studies on the function and mechanism of LHPP in tumors are insufficient. In this study, LHPP expression was found to be downregulated in both hepatocellular carcinoma (HCC) and pancreatic cancer (PC). Here, we found that LHPP could bind to epidermal growth factor receptor (EGFR) and inhibit its phosphorylation, which thereby inhibited the activation of EGFR downstream pathways ERK, AKT, and STAT3, and then weakening the ability to proliferate, invade, and migrate in HCC and PC. This paper showed a new physiological function of LHPP in inhibiting phosphorylation of EGFR and its potential anti-tumor mechanism and indicated that LHPP was a potential therapeutic target for HCC and PC.

Developing non-invasive 3D quantificational imaging for intelligent coconut analysis system with X-ray.

BACKGROUND: As one of the largest drupes in the world, the coconut has a special multilayered structure and a seed development process that is not yet fully understood. On the one hand, the special structure of the coconut pericarp prevents the development of external damage to the coconut fruit, and on the other hand, the thickness of the coconut shell makes it difficult to observe the development of bacteria inside it. In addition, coconut takes about 1 year to progress from pollination to maturity. During the long development process, coconut development is vulnerable to natural disasters, cold waves, typhoons, etc. Therefore, nondestructive observation of the internal development process remains a highly important and challenging task. In this study, We proposed an intelligent system for building a three-dimensional (3D) quantitative imaging model of coconut fruit using Computed Tomography (CT) images. Cross-sectional images of coconut fruit were obtained by spiral CT scanning. Then a point cloud model was built by extracting 3D coordinate data and RGB values. The point cloud model was denoised using the cluster denoising method. Finally, a 3D quantitative model of a coconut fruit was established. RESULTS: The innovations of this work are as follows. 1) Using CT scans, we obtained a total of 37,950 non-destructive internal growth change maps of various types of coconuts to establish a coconut data set called "CCID", which provides powerful graphical data support for coconut research. 2) Based on this data set, we built a coconut intelligence system. By inputting a batch of coconut images into a 3D point cloud map, the internal structure information can be ascertained, the entire contour can be drawn and rendered according to need, and the long diameter, short diameter and volume of the required structure can be obtained. We maintained quantitative observation on a batch of local Hainan coconuts for more than 3 months. With 40 coconuts as test cases, the high accuracy of the model generated by the system is proven. The system has a good application value and broad popularization prospects in the cultivation and optimization of coconut fruit. CONCLUSION: The evaluation results show that the 3D quantitative imaging model has high accuracy in capturing the internal development process of coconut fruits. The system can effectively assist growers in internal developmental observations and in structural data acquisition from coconut, thus providing decision-making support for improving the cultivation conditions of coconuts.

An improved Deeplab V3+ network based coconut CT image segmentation method.

Due to the unique structure of coconuts, their cultivation heavily relies on manual experience, making it difficult to accurately and timely observe their internal characteristics. This limitation severely hinders the optimization of coconut breeding. To address this issue, we propose a new model based on the improved architecture of Deeplab V3+. We replace the original ASPP(Atrous Spatial Pyramid Pooling) structure with a dense atrous spatial pyramid pooling module and introduce CBAM(Convolutional Block Attention Module). This approach resolves the issue of information loss due to sparse sampling and effectively captures global features. Additionally, we embed a RRM(residual refinement module) after the output level of the decoder to optimize boundary information between organs. Multiple model comparisons and ablation experiments are conducted, demonstrating that the improved segmentation algorithm achieves higher accuracy when dealing with diverse coconut organ CT(Computed Tomography) images. Our work provides a new solution for accurately segmenting internal coconut organs, which facilitates scientific decision-making for coconut researchers at different stages of growth.

E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2.

Both pro-oncogenic and anti-oncogenic effects of E2F2 have been revealed in different malignancies. However, the precise role of E2F2 in pancreatic cancer, in particular in relation to therapeutic intervention with gemcitabine, remains unclear. In this study, the effect of E2F2 on the proliferation and cell cycle modulation of pancreatic cancer cells, and whether E2F2 plays a role in the treatment of pancreatic cancer cells by gemcitabine, were investigated. The expression of E2F2 in pancreatic cancer was assessed by various methods including bioinformatics prediction, Western blotting, and real-time PCR. The effect of E2F2 on the proliferation and cell cycling of pancreatic cancer cells was analyzed by tissue culture and flow cytometry. In addition, the effect of E2F2 on the intervention of pancreatic cancer by gemcitabine was investigated using both in vitro and in vivo approaches. The expression of E2F2 was found to be significantly increased in pancreatic cancer tissues and cell lines. The pathogenic capacity of E2F2 lied in the fact that this transcription factor promoted the transformation of pancreatic cancer cell cycle from G1-phase to S-phase, thus enhancing the proliferation of pancreatic cancer cells. Furthermore, the expression of E2F2 was increased in pancreatic cancer cells in the presence of gemcitabine, and the augmented expression of E2F2 upregulated the gemcitabine resistance-related gene RRM2 and its downstream signaling molecule deoxycytidine kinase (DCK). The resistance of pancreatic cancer cells to gemcitabine was confirmed using both in vitro and in vivo models. In this study, E2F2 has been demonstrated for the first time to play a pro-oncogenic role in pancreatic cancer by promoting the transition of the cell cycle from G1-phase to S-phase and, therefore, enhancing the proliferation of pancreatic cancer cells. E2F2 has also been demonstrated to enhance the chemotherapy resistance of pancreatic cancer cells to gemcitabine by upregulating the expression of RRM2 and DCK that is downstream of RRM2.

Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock­in mouse model.

The SAM and SH3 domain­containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia­associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf­positive epithelial cells was also detected. An increased expression of Mitf­ and Mitf­positive cells was also demonstrated in the epithelial tissues of Y551D­SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1­mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1­Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities.

Combination of gemcitabine and erlotinib inhibits recurrent pancreatic cancer growth in mice via the JAK-STAT pathway.

Compared to single gemcitabine treatment, the combination of gemcitabine and erlotinib has shown effective response in patients with locally advanced or metastatic pancreatic cancer. However, the combination therapy has not proven effective in patients with pancreatic cancer after R0 or R1 resection. In the present study, a nude mice model of orthotopic xenotransplantation after tumor resection was established using pancreatic cancer cell lines, BxPC-3 and PANC­1. Mice were divided in four groups (each with n=12) and were treated as follows: the control group received a placebo via intraperitoneal injection (i.p.), while the other three groups were treated with gemcitabine (50 mg/kg i.p., twice a week), erlotinib (50 mg/kg oral gavage, once every three days), and combined treatment of gemcitabine and erlotinib, respectively. The treatment lasted for 21 days, after which all mice were sacrificed and tumors were examined ex vivo. We determined that the combination of gemcitabine and erlotinib inhibited recurrent tumor growth and induced apoptosis in vivo by downregulating phosphorylation levels of JAKs and STATs, which in turn downregulated the downstream proteins HIF­1α and cyclin D1, and upregulated caspase­9 and caspase­3 expression. To sum up, the combination of gemcitabine with erlotinib was effective in treating patients with pancreatic cancer after R0 or R1 resection.