Development Of Human Cancers Research Articles

Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU)

Emerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.

Abstract 851: Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study

Abstract Background: Previous studies have suggested the potential roles of dietary intakes of calcium and magnesium in human cancer development, but little is known about their associations with lung cancer risk, especially among African Americans (AAs) and low-income populations. Objectives: We conducted a nested case-control study to investigate the associations of dietary calcium and magnesium intakes with lung cancer risk among a low-income population of AAs and European Americans (EAs) in the Southeastern United States. Methods: A total of 1,560 incident lung cancer cases who were diagnosed at least two years after enrollment and 5,926 matched controls from the Southern Community Cohort Study were included. Dietary calcium and magnesium intakes were assessed using a validated food frequency questionnaire at study enrollment. Multivariate logistic regression models were used to estimate odds ratios (ORs) and corresponding confidence intervals (95% CIs) for lung cancer risk associated with intakes of calcium and magnesium, and calcium/magnesium ratios after adjusting for enrollment age, education, smoking status, and pack-years, physical activity, alcohol drinking, household income, history of chronic obstructive pulmonary disease, body mass index, energy intake, and calcium or magnesium intake. Results: Calcium intake was significantly associated with an increased risk of lung cancer among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 1.56 (1.03-2.36) and 1.14 (0.68-1.92) for AAs and EAs, respectively (p for interaction: 0.03). Meanwhile, magnesium intake was significantly associated with a reduced risk of lung cancer risk among AAs but not among EAs; ORs (95% CI) for the highest compared with lowest quartiles were 0.55 (0.35-0.89) and 0.68 (0.39-1.18), respectively (p for interaction: 0.68). ORs (95% CI) for the highest compared with the lowest quartiles for calcium/magnesium ratios were 1.21 (0.96-1.53) for AAs and 1.17 (0.85-1.61) for EAs. These associations were more evident among men and never-smokers. Conclusion: Our results suggest that higher dietary calcium and lower dietary magnesium intakes are associated with an increased risk of lung cancer, especially among AAs, raising the possibility that dietary factors may contribute to a higher risk of lung cancer among AA than EA men. Citation Format: Hyung-Suk Yoon, Xiao Ou Shu, Hui Cai, Wei Zheng, William J. Blot, Qiuyin Cai. Associations of dietary calcium and magnesium intakes with lung cancer risk among low-income Americans: Results from the Southern Community Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 851.

Abstract 756: The association between serum serine and glycine and related-metabolites with pancreatic cancer in two prospective cohort studies

Abstract Background. Serine and glycine play an important role in the folate-dependent one-carbon metabolism. The metabolism of serine and glycine has been shown to be associated with cancer cell proliferation. No prior epidemiologic study has investigated the associations for serum levels of serine, glycine and their related-metabolites with pancreatic cancer risk. Methods. Two parallel nested case-control studies derived from the Shanghai Cohort Study (with 129 cases and 258 controls) and from the Singapore Chinese Health Study (with 58 cases and 104 controls), respectively, were conducted to examine these associations. Conditional logistic regression method was used to evaluate the associations between serine, glycine and related-matabolites with pancreatic cancer risk, adjusting for potential confounders (i.e., level of education, body mass index, smoking status, alcohol consumption, history of diabetes, serum cotinine concentration, serum pyridoxal 5'-phosphate concentration (PLP), and estimated glomerular filtration rate (eGFR)). Results. In the two studies combined data, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of serine and glycine were 0.42 (0.23-0.78) and 0.39 (0.21-0.72), respectively, compared with the lowest quartile. No significant association with risk of pancreatic cancer was observed for other serine- or glycine related metabolites including cystathionine, cysteine, and sarcosine. Conclusion. The novel observation for a statistically significant inverse association for serum serine and glycine with risk of pancreatic cancer supports a protective role of these metabolites in the folate pathway against the development of pancreatic cancer in humans. With the experimental data showing the impact of serine and glycine on gut microbiota composition, [YJM1] our findings suggest that the alteration of gut microbiota may play a contributing role in reducing the risk of pancreatic cancer. Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876). HN Luu was partially supported by the University of Pittsburgh Medical Center Hillman Cancer Center start-up grant. P Paragomi was supported by the NIH T32CA186873 training grant in cancer epidemiology and prevention. W-P Koh was partially supported by the National Medical Research Council, Singapore (NMRC/CSA/0055/2013). Citation Format: Hung N. Luu, Renwei Wang, Pedram Paragomi, Joyce Y. Huang, Lesley M. Butler, Øivind Midttun, Arve Ulvik, Aizhen Jin, Yu-Tang Gao, Per M. Ueland, Woon-Puay Koh, Jian-Min Yuan. The association between serum serine and glycine and related-metabolites with pancreatic cancer in two prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 756.

Abstract 2197: Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer

Abstract Dysregulation of mRNA alternative splicing (AS) has been implicated in development and progression of hematological malignancies. How the global AS dysregulation contributes to the development and progression of solid tumors is under-studied and remains generally unclear. Here we describe the first comprehensive AS landscape in the spectrum of human prostate cancer (PCa) development, progression and therapy resistance. We find that the severity of splicing dysregulation correlates with disease progression and establish intron retention (IR) as a hallmark of PCa stemness and aggressiveness. Systematic interrogation of 274 splicing-regulatory genes (SRGs) uncovers prevalent SRG mutations associated with, mainly, copy number variations leading to mis-expression of ~68% of SRGs during PCa evolution. Consequently, we identify many SRGs as prognostic markers associated with splicing disruption and patient outcome. Interestingly, androgen receptor (AR) controls a splicing program distinct from its transcriptional regulation. The spliceosome modulator, E7107, reverses cancer aggressiveness and inhibits the growth of castration-resistant PCa (CRPC) xenograft models and of the autochthonous Hi-Myc tumors. Altogether, our studies establish aberrant AS landscape caused by dysregulated SRGs as a hallmark of PCa aggressiveness and a novel therapeutic vulnerability for CRPC. Citation Format: Dingxiao Zhang, qiang Hu, Xiaozhuo Liu, Yibing Ji, Hsueh-Ping Chao, Amanda Tracz, Jason Kirk, Silvia Buonamici, Ping Zhu, Jianmin Wang, song liu, Dean Tang. Dysregulated alternative splicing landscape identifies intron retention as a hallmark and spliceosome as a therapeutic vulnerability in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2197.

Abstract 2965: Generation of a human breast tissue mimetic organoid model

Abstract Purpose: Much effort has been focused on understanding breast cancer tumorigenesis. However, the regulation of human breast cancer development by gene mutations, hormone perturbation, external chemicals, and environmental cues is poorly understood at the molecular and cellular level. Although mouse models have been invaluable in advancing the knowledge of breast cancer tumorigenesis and progression, human breast ex vivo models comprising the breast tissue microenvironment are needed to help elucidate the underlying mechanisms of breast cancer risk factors. Here, we report a new human breast tissue mimetic organoid model. Methods: Fresh human breast tissue specimens from reduction mammaplasty reduction and prophylactic surgeries were cut and digested overnight. The breast microtissue containing stroma components were collected via centrifugation. They were then cultured in 3D using a matrix mixture containing Matrigel, collagen I, and specially formulated organoid medium. Using culture inserts, a “sandwich” method was utilized, in which we added 1 layer of matrix mixture, followed by 2 layers of organoids and matrix mixture, and a final layer of matrix mixture. Imaging analyses, including immunohistochemistry, immunofluorescence, and highly-multiplexed CODEX imaging, were used to study cellular marker expression in the organoids. Results: Our 3D culture system is distinct from previous models that reconstitute 3D mammary microstructures using isolated individual cell populations and is capable of growing patient-derived breast organoids for 3 weeks and longer. Via CODEX imaging we spatially localized more than 25 antigens for different cell types, allowing us to produce detailed characterizations of the organoid microarchitecture. Breast tissue microstructures with ducts and lobules along with stromal cell types normally found in the human breast are present. For the first time, we found that different stromal cell types grow alongside the mammary epithelium in the organoid system. The cultured breast organoids are hormone responsive and can be subcultured. We also found that BRCA1 mutant organoids are more sensitive to estrogen and progesterone treatment compared with BRCA1 wildtype, as indicated by organoid size changes. Furthermore, BRCA1 mutant organoids display unique gene expression profiles related to oxidative stress and DNA damage response. Conclusion: We have developed a 3D human breast tissue mimetic culture model that phenocopies the breast tissue microenvironment. This model will serve as the foundation for refining a breast organoid system that can faithfully recapitulate the physiology of human breast tissue. It will pave the way for a novel screening system that will test the pathogenic effects of breast cancer risk factors, providing a useful tool for elucidating the biological mechanisms of breast cancer tumorigenesis. Citation Format: Tian-Yu Lee, Nadya Nikulina, Srivarshini C. Mohan, Edward Ray, Armando Giuliano, Oliver Braubach, Xiaojiang Cui. Generation of a human breast tissue mimetic organoid model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2965.

Abstract 2465: The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression

Abstract Metabolism reprogramming and increased glycolysis of cancer are associated with rapid cell growth, motility, and resistance to drug treatment. Fructose-1, 6-bisphosphate (F-1,6-BP), an important product involvement in glucose metabolism, especially in cancer development. It is known that the essential enzymes of gluconeogenesis and glycolysis, fructose-1,6-bisphosphonates 1 (FBP1) and glycolytic enzyme aldolase A (ALDOA) expression are involved in the F-1,6-BP conversion process. Especially, increased expression of ALDOA has been identified to contribute to multiple human cancer development. However, the underlying molecular mechanism involvement of ALDOA and FBP1 on the switching of F-1,6-BP is still being uncovered. This study shows that the expression levels of ALDOA and FBP1 with an inversed correlation during the cancer progression, especially in lung adenocarcinoma and hepatocellular carcinoma. Immunoprecipitation and proteomics analyses revealed the candidates, including the anterior gradient 2 (AGR2), ubiquitin ligase gene cullin 4B (CUL4B), and telomeric repeat binding factor 1 (TERF1) are significantly correlated with ALDOA and FBP1 expression. We designed a specific peptide to interfere the interaction of candidates on both ALDOA and FBP1. Moreover, we evaluate the relative glucose metabolism events. Further, we raised the hypothesis that these candidates may serve as a modulator to regulate the conversion of F-1,6-BP and contribute to cancer progression, which can be used as a therapeutic target for further research. Citation Format: Chien Hsiu Li, Yu-Chan Chang, Michael Hsiao. The opposing regulation of ALDOA and FBP1 in Glucose metabolism contribute to cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2465.

SPATIAL DISTRIBUTION, POLLUTION, AND HEALTH RISK ASSESSMENT OF HEAVY METAL IN INDUSTRIAL AREA SOILS OF ULAANBAATAR, MONGOLIA

Abstract. The heavy metal pollution of urban soil of industrial area and its impact on human healths becoming one of the environmental problems in Ulaanbaatar city of Mongolia. The purpose of this study was to determine spatial distribution and health risk of heavy metal pollution in soils surrounding area of leather processing factory and wastewater treatment plants (WWTP) of Ulaanbaatar city. Mapping the spatial distribution of contaminants in soils is the basis of pollution evaluation and risk control. Interpolation methods are extensively applied in the mapping processes to estimate the heavy metal (As, Zn, Pb, Cd, Cr, Cu) concentrations of topsoils. The average concentrations of Cr, Ni, Pb, Zn, Cu and As were 1986.9, 110.5, 111.0, 110.5, 53.5, 16.4 mg/kg, respectively. According to result as the soil pollution index with spatial distribution, a high pollution level for Cr while Zn, Cu and Pb have medium pollution levels. The soil pollution index (PI) values of heavy metals of study areas are, following descending orders Cr > Zn > Cu > Pb > As > Ni. The potential ecological risk of Cr, Cu, Pb, As indicated high ecological risk in the study area. The Hazard index values for almost all the metals were higher than 1, it is indicating a carcinogenic risk for children and adults. The risk index values of two metals (Cr, As) were contribute to a higher risk of development of cancer in humans. Heavy metal contamination can occur when soil particles are swept away from the initial pollution areas by the wind. Therefore, it is necessary to take measures to reduce soil pollution and encourage rehabilitation.

Circular RNA hsa_circ_0110389 promotes gastric cancer progression through upregulating SORT1 via sponging miR-127-5p and miR-136-5p

Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p–SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p–SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.

Long non-coding RNA SNHG1 suppresses cell migration and invasion and upregulates SOCS2 in human gastric carcinoma

Gastric carcinoma (GC) is one of the most common malignancies and the third leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. In this study, we investigated the clinical significance and function of lncRNA SNHG1 in GC. SNHG1 was significantly downregulated in GC tumor tissues compared with adjacent noncancerous tissues. Overexpression of SNHG1 in BGC-823 cells remarkably inhibited not only cell proliferation, migration, invasion in vitro, but also tumorigenesis and lung metastasis in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Conversely, inhibition of SNHG1 by transfection of siRNA in AGS cells resulted in opposite phenotype changes. Mechanically, SNHG1 was found interacted with ILF3, NONO and SFPQ. RNA-seq combined with bioinformatic analysis identified a serial of downstream genes of SNHG1, including SOCS2, LOXL2, LTBP3, LTBP4. Overexpression of SNHG1 induced SOCS2 expression whereas knockdown of SNHG1 decreased SOCS2 expression. In addition, knockdown of SNHG1 promoted the activation of JAK2/STAT signaling pathway. Taken together, our data suggested that SNHG1 suppressed aggressive phenotype of GC cells and regulated SOCS2/JAK2/STAT pathway.

Melatonin inhibits gallbladder cancer cell migration and invasion via ERK-mediated induction of epithelial-to-mesenchymal transition.

Melatonin is a naturally occurring molecule secreted by the pineal gland that exhibits antitumor properties and prevents the development of human cancer. However, little is known regarding the effects of melatonin on gallbladder cancer (GBC) cells. The present study aimed to investigate the role of melatonin on the prevention of GBC cell invasion. The GBC cell line, GBC-SD, was treated with different concentrations of melatonin for different time periods, and the data indicated that melatonin markedly inhibited the invasion of GBC cells. Following treatment of GBC cells with melatonin, the protein levels of the epithelial marker, E-cadherin, significantly increased, while the expression levels of the mesenchymal markers, N-cadherin, Snail and vimentin, notably decreased. In addition, melatonin inhibited the phosphorylation of ERK1/2. Following treatment of the cells with the ERK activator, tert-Butylhydroquinone, the anti-invasive effects of melatonin were reversed by rescuing epithelial-to-mesenchymal transition in GBC cells. Taken together, these results suggest that melatonin inhibits GBC invasiveness by blocking the ERK signaling pathway. Thus, melatonin may be used as a potential novel cancer therapeutic drug for the treatment of GBC.

Inhibiting USP14 ameliorates inflammatory responses in trophoblast cells by suppressing MAPK/NF-κB signaling.

BackgroundPreeclampsia can cause severe consequences for pregnant women and infants, and developing effective medicine or methods to prevent or treat patients with preeclampsia is urgently needed. Ubiquitin‐specific protease 14 (USP14) has emerged as a critical regulator in the development of human cancers and neurodegenerative diseases. However, its role in preeclampsia remains elusive.MethodsThe expression of USP14 in placental tissues from healthy donors and preeclampsia patients were determined by quantitative reverse transcription PCR assay. The protein levels of targeted genes were evaluated by Western blotting assay. Small interfering RNA‐mediated gene knockdown was used to reduce USP14 expression in trophoblast cell lines.ResultsThe expression levels of USP14 and proinflammatory cytokine were substantially upregulated in placental tissues from preeclampsia patients. Knockdown or inhibition of USP14 significantly abrogated hypoxia/reoxygenation‐induced upregulation of nuclear factor kappa B (NF‐κB) activation and proinflammatory cytokine production.ConclusionOur results suggested that USP14 promotes proinflammatory cytokine production through activation of NF‐κB. Developing drugs targeting USP14 may be beneficial for the prevention or treatment of patients with preeclampsia.

Insights into Temperature and Hypoxia Tolerance in Cowpea Weevil via HIF-1.

Cowpea weevil (Callosobruchus maculatus) is a major pest that leads to severe damage of the stored leguminous grains. Several management approaches, including physical barriers, biological or chemical methods, are used for controlling bruchid in cowpea. These methods usually target the metabolically active state of weevil. However, it becomes less effective at early stages as egg, larva, or pupa under low temperature and oxygen conditions. Since hypoxia-inducible factor-1 (HIF-1) is known to coordinate multiple gene responses to low oxygen or low temperature signals, we examined the HIF-1α gene expression under low temperature and hypoxic treatments. At −20 °C, it took 4 h to reduce the survival rate for eggs, larvae, and pupae down to 10%, while at 4 °C and 15 °C, the survival rate remained higher than 50% even after 128 h as HIF-1α gene expression peaked at 15 °C. Moreover, HIF-1 protein offers a valuable target for early stage pest control complementary to traditional methods. In particular, HIF-1 inhibitor camptothecin (CPT), one of the five HIF-1 inhibitors examined, achieved a very significant reduction of 96.2% and 95.5% relative to the control in weevil survival rate into adult at 4 °C and 30 °C, respectively. Our study can be used as one model system for drug development in virus infections and human cancer.

The Emerging Role of Thymopoietin-Antisense RNA 1 as Long Noncoding RNA in the Pathogenesis of Human Cancers.

Long noncoding RNAs (lncRNAs) play essential roles in the occurrence and development of multiple human cancers. An accumulating body of researches have investigated thymopoietin antisense RNA 1 (TMPO-AS1) as a newly discovered lncRNA, which functions as an oncogenic lncRNA that is upregulated in various human malignancies and associated with poor prognosis. Many studies have detected abnormally high expression levels of TMPO-AS1 in multiple cancers, such as lung cancer, breast cancer, colorectal cancer (CRC), hepatocellular carcinoma, CRC, gastric cancer, ovarian cancer, thyroid cancer, esophageal cancer, Wilms tumor, cervical cancer, retinoblastoma, bladder cancer, osteosarcoma, and prostate cancer. TMPO-AS1 has been subsequently demonstrated to play a pivotal role in tumorigenesis and progression. The aberrantly expressed TMPO-AS1 acts as a competing endogenous RNA (ceRNA) that inhibits miRNA expression, thus activating the expression of downstream oncogenes. This study comprehensively summarizes the aberrant expressions of TMPO-AS1 as reported in the current literature and explains the relevant biological regulation mechanisms in carcinogenesis and tumor progression. Corresponding studies have indicated that TMPO-AS1 has a potential value as a promising biomarker or a target for cancer therapy.

The role of long non-coding RNA BCAR4 in human cancers.

Long non-coding RNA (lncRNA) is a type of non-coding RNA with length of nucleotides > 200bp. Increasing evidences show that lncRNA breast cancer antiestrogen resistance 4 (BCAR4) plays an important role in the occurrence and development of various human cancers. It is found that BCAR4 is highly expressed in diverse tumor tissues and cells, and the high expression of BCAR4 is usually associated with poor prognosis. BCAR4 is considered as an oncogene in human cancers. By competing endogenous RNA (ceRNA) mechanism and regulating different signaling pathways, BCAR4 participates in the proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT), metastasis and tumorigenesis of different cancers. In addition, overexpression of BCAR4 promotes drug resistance of tumor cells. Therefore, BCAR4 is a promising biomarker for cancer diagnosis and prognosis, and it is a potential target for cancer therapy. This paper reviews studies focusing on the relationship between BCAR4 and cancers in recent years and aims to summarize the effect and mechanism of BCAR4 in human cancers.

LncRNA DLEU1 Contributes to the Growth and Invasion of Colorectal Cancer via Targeting miR-320b/PRPS1.

Growing evidences suggest that long non-coding RNAs (lncRNAs) are closely correlated to the development of human cancer, such as colorectal cancer (CRC). A previous report suggested that DLEU1 accelerated CRC development. However, DLEU1’s underlying mechanism in CRC remains unclear. In our study, the level of DLEU1 in CRC tissues is investigated by qRT-PCR. Our data exhibited that DLEU1 level was observably increased in CRC tissues and CRC cell lines and was closely associated with bad prognosis of CRC patients. CRC cell proliferation was repressed by sh-LncRNA DLEU1, whereas cell apoptosis was markedly stimulated. Moreover, knockdown of DLEU1 inhibited cell migration and invasion. Mechanistically, through interacting with miR-320b in CRC, DLEU1 promoted the level of PRPS1 which was a target of miR-320b. The rescue experiment confirmed that knockdown of DLEU1 repressed cell proliferation, migration and invasion while stimulated cell apoptosis via miR-320b/phosphoribosyl pyrophosphate synthetase 1 (PRPS1) axis. Meanwhile, the data of xenograft model exhibited that inhibition of DLEU1 suppressed tumor growth in vivo. In summary, DLEU1 knockdown may repress PRPS1 expression via miR-320b, and then repress cell proliferation, migration and invasion while stimulate cell apoptosis. Our research may provide a novel target for the treatment of CRC.

SCUBE3 serves as an independent poor prognostic factor in breast cancer

BackgroundAccumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear.MethodsThe clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein–protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer.ResultsWe found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20–6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06–3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression.ConclusionsThese findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.

CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression

ABSTRACT Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer. Abbreviations: ATG: autophagy-related BECN1: beclin 1 CHX: cycloheximide CoIP: co-immunoprecipitation CUL3: cullin 3 IP: immunoprecipitation MS: mass spectrometry PtdIns3K: phosphatidylinositol3-kinase UPS: ubiquitin-proteasome system

Intense terahertz pulses inhibit Ras signaling and other cancer-associated signaling pathways in human skin tissue models

Terahertz (THz) radiation has shown unique advantages in biomedical applications for novel diagnostic technologies due to the high sensitivity to molecular structure and chemical concentration. However, emerging evidence shows that intense pulses of THz radiation can induce significant non-thermal biological effects that must be characterized. In human skin exposed to intense THz pulses, relatively large responses characterized by differential gene expression profiles are observed. These data are analyzed by signaling pathway perturbation analysis to predict phenotypic endpoints and dysregulatory effects on cancer-related processes. The activities of several important pathways that drive the initiation, development, and progression of many human cancers are predicted to be suppressed, and this effect is intensity-dependent. Some affected pathways are targets for current and emerging anti-cancer therapies. In particular, the activity of the Ras signaling and Calcium signaling pathways is predicted to be significantly inhibited. These results indicate the possibility of an additional therapeutic mechanism of intense THz pulses, due to the potential for targeted suppression of pro-mitotic activity in diseased tissue.

Stabilization of proto‐oncoprotein ZBTB7A by HSP90 is reversed by p53/KLHL20 proteasomal degradation system upon HSP90 inhibition

ZBTB7A is overexpressed in many human cancers, and is considered a major oncogenic driver. ZBTB7A plays important roles in tumorigenesis by regulating transcription of genes involved in cell survival and proliferation, apoptosis, invasion, and migration/metastasis, key biological capabilities for development of human cancer. One critically unresolved issue is a lack of insight into the mechanisms underlying the aberrant expression and function of ZBTB7A in cancer cells. To that end, we found that HSP90 inhibition decreased ZBTB7A expression in a variety of human cancer cells. ZBTB7A interacts with and is stabilized by HSP90 by inhibition of the ubiquitin-mediated proteasomal degradation pathway. Functional inhibition of HSP90 by 17-AAG, resulted in p53-dependent proteolysis of ZBTB7A, via increased p53 expression and upregulation of the CUL3-dependent E3 ubiquitin ligase, KLHL20. ZBTB7A degradation resulted in derepression of ZBTB7A target genes regulating cell cycle and inhibition of cell proliferation. Our study also revealed a novel function of p53 counteracting proto-oncoprotein ZBTB7A.

LINC02257, an Enhancer RNA of Prognostic Value in Colon Adenocarcinoma, Correlates With Multi-Omics Immunotherapy-Related Analysis in 33 Cancers.

Accumulated evidence supports that long non-coding RNAs (lncRNAs) are involved significantly in the development of human cancers. Enhancer RNAs (eRNAs), a subtype of lncRNAs, have recently attracted much attention about their roles in carcinogenesis. Colon adenocarcinoma is one of the most commonly diagnosed tumors with unfavorable prognosis. It highlights the great significance of screening and identifying novel biomarkers. More importantly, it remains to be elucidated with respect to the function of eRNAs in colon adenocarcinoma, as is in pan-cancers. The expression of LINC02257 was determined based on the data obtained from The Cancer Genome Atlas (TCGA). Further evaluation was performed on the basis of the following analyses: clinicopathology and survival analysis, gene ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, as well as multi-omics immunotherapy-related analysis and co-expression analysis. The statistical analysis was conducted in R software, and immune cell infiltration of LINC02257 expression in cancers was investigated by using the CIBERSORT algorithm. By large-scale data mining, our study highlighted that a total of 39 eRNA genes were associated with colon adenocarcinoma prognosis, among which 25 eRNAs showed significant associations with their predicted target genes. LINC02257 was identified as the most significant survival-associated eRNA, with DUSP10 as its target gene. Besides, the high expression of LINC02257 in colon adenocarcinoma was more vulnerable to unfavorable prognosis and correlated with various clinical characteristics. GO and KEGG analyses revealed that LINC02257 was closely correlated with extracellular matrix organization via the PI3K-Akt signaling pathway. Besides, LINC02257 expression correlated with a multi-omics analysis of 33 cancer types, such as survival analysis [overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI)] and immunotherapy-related analysis [tumor microenvironment (TME), tumor mutational burden (TMB), and microsatellite instability (MSI)]. Finally, we investigated the co-expression genes of LINC02257 and its potential signaling pathways across different cancer types. LINC02257 is screened and can function as an independent prognostic biomarker through the PI3K-Akt signaling pathway for colon adenocarcinoma. Simultaneously, LINC02257 may be a multifaceted and significant immunotherapy-related eRNA in different cancers.