Collagen XVII promotes dormancy of colorectal cancer cells by activating mTORC2 signaling.

Tumor dormancy is the underpinning for cancer relapse and chemoresistance, leading to massive cancer-related death in colorectal cancer (CRC). However, our comprehension of the mechanisms dictating tumor dormancy and strategies for eliminating dormant tumor cells remains restricted. In this study, we identified that collagen XVII (COL17A1), a hemidesmosomal transmembrane protein, can promote the dormancy of CRC cells. The upregulation of COL17A1 was observed to prolong quiescence periods and diminish drug susceptibility of CRC cells. Mechanistically, COL17A1 acts as a scaffold, enhancing the crosstalk between mTORC2 and Akt, thereby instigating the mTORC2-mediated dormant signaling. Notably, the activation of mTORC2 is contingent upon the intracellular domain of COL17A1, regardless of its ectodomain shedding. Our findings underscore a pivotal role of the COL17A1-mTORC2 axis in CRC dormancy, suggesting that mTORC2-specific inhibitors may hold therapeutic prospects for the eradication of dormant tumor cells.

Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.

Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

Study on the mechanism of sodium ion inhibiting citric acid fermentation in Aspergillus niger.

Excessive sodium significantly inhibits citric acid fermentation by Aspergillus niger during the recycling of citric acid wastewater. This study aimed to elucidate the inhibition mechanism at the interface of physiology and transcriptomics. The results showed that excessive sodium caused a 22.3 % increase in oxalic acid secretion and a 147.6 % increase in H+-ATPase activity at the 4 h fermentation compared to the control. Meanwhile, a 13.1 % reduction in energy charge level and a 15.2 % decline in NADH content were found, which implied the effects on carbon metabolism and redox balance. In addition, transcriptomic analysis revealed that excessive sodium altered the gene expression profiles related to ATPase, hydrolase, and oxidoreductase, as well as pathways like glyoxylate metabolism, and transmembrane transport. These findings gained insights into the metabolic regulation of A. niger response to environmental stress and provided theoretical guidance for the construction of sodium-tolerant A. niger for industrial application.

CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

Cellular Network Power Allocation Algorithm Based on Deep Reinforcement Learning and Artificial Intelligence.

In the shortest path planning problem, the old algorithm usually has many defects, such as the robot's cognition being contrary to reality, the lack of practical operation feasibility, or the limitation of problem processing. Nowadays, with deep learning, artificial intelligence algorithms tend to be mature; it has become a mainstream trend to adopt end-to-end learning system instead of traditional old algorithms. In recent years, with the rise of the Internet of things emerging technology industry and the explosive surge of network data traffic, the drawback is the increasingly severe shortage of wireless spectrum resources. In order to effectively reduce the cochannel interference of D2D communication technology in the system and enhance the useable range of the cellular network, it is necessary to distribute the useful and efficient cellular resources of the system. In this article, we will study the D2D users and the selection scheme of D2D users' transmission power control mode and allocate the spectrum resources in the uplink of the cellular users in the communication network. In order to reduce the cochannel interference in a cellular network and improve the spectrum utilization of the system, the research direction of this article is to solve the problem of user communication resource allocation in a single-cell hybrid cellular network.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

Glipizide Combined with ANP Suppresses Breast Cancer Growth and Metastasis by Inhibiting Angiogenesis through VEGF/VEGFR2 Signaling.

BACKGROUND: Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis. METHODS: This study aimed at investigating the effect of glipizide combined with ANP on breast cancer. Glipizide, ANP, or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed. RESULTS: Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling. CONCLUSION: These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as an effective agent for the treatment of breast cancer by targeting tumor-induced angiogenesis.

PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

Production of butanol from distillers' grain waste by a new aerotolerant strain of Clostridium beijerinckii LY-5.

A new aerotolerant strain of Clostridium beijerinckii LY-5 was isolated from the pit mud of the Chinese Baijiu-making process for butanol production. Plackett-Burman design and artificial neural network were used to optimize the fermentation medium and a total of 13.54 ± 0.22 g/L butanol and 19.91 ± 0.52 g/L ABE were attained under aerotolerant condition. Moreover, distillers' grain waste (DGW), the main by-product in the Baijiu production process, was utilized as potential substrate for butanol production. DGW was hydrolyzed by α-amylase and glucoamylase and then fermented after a detoxifying process of overliming. Butanol and ABE concentrations were 9.02 ± 0.18 and 9.57 ± 0.19 g/L with the yield of 0.21 and 0.23 g/g sugar, respectively. The higher ratio of butanol to ABE might be caused by the inhibitors in DGW medium affecting the metabolic pathways of C. beijerinckii LY-5 and approximately 1.48 ± 0.04 g/L isopropanol was found at the end of fermentation. This work highlights the feasibility of using DGW as a promising feedstock for butanol production by a new aerotolerant strain of C. beijerinckii LY-5, with benefit to the environment.

Decylubiquinone suppresses breast cancer growth and metastasis by inhibiting angiogenesis via the ROS/p53/ BAI1 signaling pathway.

Breast cancer is one of the most common cancers worldwide with a rising incidence, and is the leading cause of cancer-related death among females. Angiogenesis plays an important role in breast cancer growth and metastasis. In this study, we identify decylubiquinone (DUb), a coenzyme Q10 analog, as a promising anti-breast cancer agent through suppressing tumor-induced angiogenesis. We screened a library comprising FDA-approved drugs and found that DUb significantly inhibits blood vessel formation using in vivo chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models. DUb was further identified to inhibit angiogenesis in the rat aortic ring and Matrigel plug assay. Moreover, DUb was found to suppress breast cancer growth and metastasis in the MMTV-PyMT transgenic mouse and human xenograft tumor models. To explore whether the anticancer efficacy of DUb was directly corrected with tumor-induced angiogenesis, the MDA-MB-231 breast cancer assay on the CAM was performed. Interestingly, DUb significantly inhibits the angiogenesis of breast cancer on the CAM. Brain angiogenesis inhibitor 1 (BAI1), a member of the G protein-coupled receptor (GPCR) adhesion subfamily, has an important effect on the inhibition of angiogenesis. Further studies demonstrate that DUb suppresses the formation of tubular structures by regulating the reactive oxygen species (ROS)/p53/BAI1 signaling pathway. These results uncover a novel finding that DUb has the potential to be an effective agent for the treatment of breast cancer by inhibiting tumor-induced angiogenesis.

R5, a neutralizing antibody to Robo1, suppresses breast cancer growth and metastasis by inhibiting angiogenesis via down-regulating filamin A.

Breast cancer (BC) is one of the most common cancers among women in both developed and developing countries with a rising incidence. Using the MMTV-PyMT transgenic mouse model and xenografted breast cancer model, we found that R5, a neutralizing antibody to Robo1, significantly inhibited BC growth and metastasis. Angiogenesis is involved in the growth and metastasis of BC. Interestingly, R5 significantly decreases microvessel density in BC tissues, and inhibits blood vessel formation and development in in vivo chick embryo chorioallantoic membrane (CAM), yolk sac membrane (YSM) and Matrigel plug models. To investigate whether its anti-breast cancer efficacy is ascribed to its direct antiangiogenic properties, xenografted breast cancer model on CAM was established. Furthermore, R5 significantly reduces the tube formation of the vascular plexus on xenografted breast tumor on CAM. R5 also suppresses the migration and the tubular structure formation of human umbilical vein endothelial cells (HUVECs) by down-regulating the expression of filamin A (FLNA). These findings show that R5 has the potential to be a promising agent for the treatment of BC by suppressing the tumor-induced angiogenesis.

Generation and Biological Characteristics of a Mouse Model of Breast Cancer that Copresents with Diabetes Mellitus.

Both diabetes and breast cancer are common diseases worldwide, and diabetes is also linked to higher rates of breast cancer. Epidemiological data also indicate that diabetes may be one of the risk factors for breast cancer. However, the effect of diabetes on breast cancer progression in vivo is rarely reported. We established an ideal animal model of breast cancer using transgenic MMTV-PyMT mice, which spontaneously developed breast cancer. In this model, the animals copresented with diabetes mellitus, which allowed us to study the effect of high glucose on breast cancer. Compared with MMTV-PyMT mice without diabetes, MMTV-PyMT mice with diabetes developed heavier tumors and exhibited greater tumor volumes. Furthermore, high glucose promoted the invasiveness and metastasis of breast cancer in MMTV-PyMT mice. This breast cancer model in which mice copresented with diabetes provides a useful tool to study the effect of diabetes on breast cancer. Anat Rec, 302:269-277, 2019. © 2018 Wiley Periodicals, Inc.

HMGA1 Overexpression is Associated With the Malignant Status and Progression of Breast Cancer.

Breast cancer is the most common malignant tumor among women, and the incidence and mortality of breast cancer has rapidly increased in recent years. Studies have indicated that high mobility group A1 (HMGA1), an important member of the HMGA family, plays a role in the pathogenesis and progression of malignant tumors, including breast cancer. This study aims to evaluate the effect of HMGA1 in breast cancer. Interestingly, we found that HMGA1 expression was significantly higher in breast cancer tissues than in adenoma tissues and closely correlated with the clinical stage and histological grade in breast cancer patients. Further study showed that HMGA1 knockdown inhibited the proliferation and migration of breast cancer cells. Thus, the results demonstrated that HMGA1 could act as an independent prognostic indicator in breast cancer. HMGA1 expression was closely correlated with the clinical stage, histological grade, and tumor size in breast cancer patients and breast cancer progression in transgenic MMTV-PyMT mice. Anat Rec, 301:1061-1067, 2018. © 2018 Wiley Periodicals, Inc.

Association Between Tissue Inhibitor of Metalloproteinase-3 Gene Methylation and Gastric Cancer Risk: A Meta-Analysis.

BACKGROUND: The tumor suppressor gene tissue inhibitor of metalloproteinase-3 (TIMP-3) has been reported to be frequently and significantly downregulated in gastric cancer, and its downregulation is correlated with hypermethylation in its promoter region. However, the association between TIMP-3 methylation and gastric cancer risk remains unclear. AIM: In this study, we assessed the relationship between TIMP-3 promoter methylation and gastric cancer risk by performance of a meta-analysis. METHODS: Relevant studies were identified in a comprehensive literature search using PubMed, Embase, and Web of Science databases. The strength of the association between TIMP-3 methylation and the risk of gastric cancer was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI). The heterogeneity among studies was tested using the Q-statistics and I(2) metric. The publication bias was examined by Begg's funnel plots and Egger's linear regression test. RESULTS: A total of 1096 subjects from eight studies were included in the present meta-analysis. Overall, a significant association between TIMP-3 methylation and gastric cancer risk was observed (OR = 8.65; 95% CI 4.31-17.37; p < 0.001). Stratified analyses by ethnicity, sample materials, and detection methods also revealed increased gastric cancer risk in individuals harboring methylated TIMP-3. Moreover, no publication bias was detected in the present meta-analysis. CONCLUSIONS: Our results show a positive correlation between TIMP-3 promoter methylation and gastric cancer risk and indicated that TIMP-3 promoter methylation may be used as a molecular marker for gastric cancer.

[Effect of norcantharidin's derivative Nd3 on proliferation of human ovarian cancer cell line SKOV3 and its possible mechanisms].

BACKGROUND & OBJECTIVE: Norcantharidin (NCTD), the demethylated form of cantharidin, can inhibit the proliferation of many kinds of cancer cells, but its effect is milder than those of other drugs. This study was to explore the inhibitory effect of Nd3, a derivative of norcantharidin, on the proliferation of human ovarian cancer cell line SKOV3, compare its antitumor effect with that of norcantharidin, and investigate its possible molecular mechanisms. METHODS: SKOV3 cells were treated with Nd3 and norcantharidin, separately. Cell proliferation was evaluated by sulforhodamine B (SRB) assay. Cell cycle distribution and apoptosis were detected by flow cytometry. The expression of Cdc2, Cyclin B1, Bax, and Bcl-2 was detected by Western blot. RESULTS: When treated with 2.5, 5, 10, 20, 30, and 40 micromol/L Nd3 for 48 h, the inhibition rates of SKOV3 cells were 27.3%, 34.1%, 53.3%, 64.3%, 83.3%, and 96.7%, respectively, which were significantly higher than that of negative control cells (P<0.001). The 50% inhibition concentration of Nd3 was (25.1+/-2.3) micromol/L at 24 h, (21.8+/-2.8) micromol/L at 36 h, and (20.4+/-3.3) micromol/L at 48 h. When treated with 10, 20, 30, and 40 micromol/L Nd3 for 48 h, SKOV3 cells were arrested at G2/M phase at rates of 14.3%, 20.2%, 26.2%, and 27.9%; when treated with 30 micromol/L Nd3 for 12, 24, 36, and 48 h, the proportions of SKOV 3 cells at G2/M phase were 19.8%, 26.6%, 27.8%, and 32.0%. When treated with 40 micromol/L Nd3 for 48 h, the apoptosis rate of SKOV3 cells was significantly higher than that of control cells [(17.9+/-4.4)% vs. (2.5+/-2.8)%, P<0.01]. After treatment of Nd3, the expression of Cdc2, Cyclin B1, and Bcl-2 were down-regulated, and the expression of Bax was up-regulated. CONCLUSIONS: Nd3 inhibits SKOV3 cell proliferation more than norcantharidin does, blocks cell cycle at G2/M phase, and induces apoptosis. The antitumor mechanism of Nd3 is related to the changes of Cdc2, Cyclin B1, Bax, and Bcl-2 expression.

Volatilization behaviors of diesel oil from the soils.

The volatilization of diesel oil, Shengli crude oil and 90 # gasoline on glass surface of petri dishes were conducted at the ambient temperature of 25 degrees C. Diesel oil evaporates in a power manner, where the loss of mass is approximately power with time. 90 # gasoline evaporates in a logarithmic with time. Where as the volatilization of Shengli crude oil fit either the logarithmic or power equation after different time, and has similar R2. And the effects of soil type and diesel oil and water content on volatilization behavior in unsaturated soil were studied in this paper. Diesel oil and water content in the soils play a large role in volatilization from soils. Appropriate water helps the wicking action but too much water stops it. The wicking action behaves differently in four different types of soils in the same volatilization experiment of 18% diesel oil content and air-dry condition.