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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 361 records · Page 20
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Downregulation of cytochrome c oxidase subunit 7A1 expression is important in enhancing cell proliferation in adenocarcinoma cells

Mitochondrial Dysfunction has been implicated in multiple human diseases, including cancer. Among all cancer, lung cancer is the most common type of cancer worldwide with low survival rates. Mammals possess multiple subunits of the mitochondrial enzyme Cytochrome C oxidase (COX). The COX subunits are expressed in a tissue specific manner and have been implicated in cancer cell metabolism although their molecular and regulatory mechanisms are not clearly understood. In this study, we aimed at identifying novel gene signatures in lung cancer. We performed extensive analysis of seven different Gene Expression Omnibus (GEO) datasets pertaining to different stages of lung adenocarcinoma and identified that multiple subunits of COX genes are differentially expressed in these patients. Amongst all COX genes, the expression of COX7A1 gene was observed to be highly down regulated in these patients. In order to validate the GEO datasets, we looked at the expression of multiple COX genes using quantitative real time PCR (qPCR) using human lung adenocarcinoma cell line A549. Our results confirmed that COX 7A1 gene expression was indeed highly reduced in these cells. Overexpression of COX7A1 in human lung cancer cells led to inhibition of cell proliferation and increase in cell death via apoptosis. These results indicated that low level of COX7A1 gene expression is essential to regulate cell viability and inhibit cell death in lung adenocarcinoma. Our study has identified COX7A1 as a novel gene that might play a crucial role in the etiology of lung adenocarcinoma and can serve as a biomarker for lung cancer disease progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Sterol regulatory element-binding protein 1 inhibitors decrease pancreatic cancer cell viability and proliferation

Sterol regulatory element-binding protein1 (SREBP1) is a key regulatory factor that controls lipid homeostasis. Overactivation of SREBP1 and elevated lipid biogenesis are considered the major characteristics in malignancies of prostate cancer, endometrial cancer, and glioblastoma. However, the impact of SREBP1 activation in the progression of pancreatic cancer has not been explored. The present study examines the effect of suppression of SREBP1 activation by its inhibitors like fatostatin and PF429242 besides analyzing the impact of inhibitory effects on SREBP1 downstream signaling cascade such as fatty acid synthase (FAS), hydroxymethylglutaryl-CoA reductase (HMGCoAR), stearoyl-CoA desaturase-1 (SCD-1), and tumor suppressor protein p53 in MIA PaCa-2 pancreatic cancer cells. Both fatostatin and PF429242 inhibited the growth of MIA PaCa-2 cells in a time and concentration-dependent manner with maximal inhibition attained at 72 h time period with IC{sub 50} values of 14.5 μM and 24.5 μM respectively. Detailed Western blot analysis performed using fatostatin and PF429242 at 72 h time point led to significant decrease in the levels of the active form of SREBP1 and its downstream signaling proteins such as FAS, SCD-1 and HMGCoAR and the mutant form of tumor suppressor protein, p53, levels in comparison to the levels observed in vehicle treated control group of MIA PaCa-2 pancreatic cells over the same time period. Our in vitro data suggest that SREBP1 may contribute to pancreatic tumor growth and its inhibitors could be considered as a potential target in the management of pancreatic cancer cell proliferation. - Highlights: • A significant increase in SREBP1 levels was observed in MIA PaCa-2 cells. • Fatostatin and PF429242 suppress SREBP1 activation and its downstream signaling proteins expression. • The inhibition of SREBP1reduces tumor suppressor protein p53 in MIA PaCa-2 cells. • SREBP1 inhibition may be beneficial in treatment of pancreatic cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer

Circulating lncRNAs have been defined as a novel biomarker for non-small cell lung cancer (NSCLC), MALAT-1 was first identified lncRNA that was related to lung cancer metastasis. However, the relationship between exosomal lncRNAs and the diagnosis and prognosis of NSCLC was poorly understood. The aim of this study is to evaluate the clinical significance of serum exosomal MALAT-1 as a biomarker in the metastasis of NSCLC. In this study, we firstly isolated the exosomes from healthy subjects and NSCLC patients. Then we measured the expression levels of MALAT-1 contained in exosomes, and found that exosomal MALAT-1 was highly expressed in NSCLC patients, more importantly, the levels of exosomal MALAT-1 were positively associated with tumor stage and lymphatic metastasis. In addition, we decreased MALAT-1 expression by short hairpin RNA and conducted a series of assays including MTT, cell cycle, colony formation, wound-healing scratch and Annexin/V PI by flow cytometry in human lung cancer cell lines. These in vitro studies demonstrated that serum exosome-derived long noncoding RNA MALAT-1 promoted the tumor growth and migration, and prevented tumor cells from apoptosis in lung cancer cell lines. Taken together, this study shed a light on utilizing MALAT-1 in exosomes as a non-invasive serum-based tumor biomarker for diagnosis and prognosis of NSCLC. - Highlights: • serum MALAT-1 contained in exosomes is upregulated in NSCLC patients. • Exosomal MALAT-1 was positively associated with TNM stage and lymphatic node metastasis. • MALAT-1 knockdown inhibited cell proliferation, colony formation and cell migration. • MALAT-1 knockdown induced cell cycle arrest and cell apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. Circular RNA (circRNA) is a unique class of RNA transcribed by RNA polymerase II characterized by jointing 3′ and 5′ ends together via exon or intron circularization. However, the molecular functions of circRNAs in prostate cancer have rarely been explored. In present study, we found circ-SMARCA5 was up-regulated in prostate cancer samples compared to match normal tissues. We also observed circ-SMARCA5 expression was significantly induced after DHT treatment. Functional experiments showed circ-SMARCA5 acted as an oncogene in prostate cancer by promoting cell cycle and inhibiting cell apoptosis. We thought this study provided useful information for exploring circRNAs as potential therapeutic and prognostic targets for prostate cancer. - Highlights: • To our knowledge, this is the first study to explore the molecular functions of circRNA in prostate cancer. • Our study showed that circ-SMARCA5 promoted cell proliferation and inhibited cell apoptosis in prostate cancer. • circ-SMARCA5 was for the first time reported as an androgen-responsive circRNA. • circ-SMARCA5 was for the first time reported to be up-regulated in prostate cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA CCND2-AS1 promotes proliferation, migration, and invasion in papillary thyroid carcinoma

In decades, a lot of long non-coding RNAs (LncRNAs) have been proven to exert influences on tumorigenesis in vitro and in vivo. Many lncRNAs have been reported as effective therapeutic targets and biomarkers in various cancers. However, whether LncRNAs are associated with the progression of PTC remains largely unknown. In this study, we measured the expression of CCND2-AS1 in PTC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR).We found that CCND2-AS1 expression was significantly over-expressed in PTC cell lines compared to normal thyroid epithelial cells. Gain-and loss-of-function experiments were performed to investigate the role of CCND2-AS1 in PTC cells. In vitro experiments, we proved that CCND2-AS1 knockdown in TPC1 significantly suppressed cell proliferation, migration, and invasion, while CCND2-AS1 overexpression in BCPAP had the opposite effects. Meanwhile, we also found that CCND2-AS1 could regulate N-cadherin and Vimentin expression, which may influence invasion and migration. Our findings indicate that the lncRNA CCND2-AS1 is a gene associated with PTC and might become a potential therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MAD2-p31comet axis deficiency reduces cell proliferation, migration and sensitivity of microtubule-interfering agents in glioma

Mitotic arrest deficient-like-1 (MAD2, also known as MAD2L1) is thought to be an important spindle assembly checkpoint protein, which ensures accurate chromosome segregation and is closely associated with poor prognosis in many cancer. As a MAD2 binding protein, p31{sup comet} counteracts the function of MAD2 and leads to mitotic checkpoint silence. In this study, we explore the function of MAD2-p31{sup comet} axis in malignant glioma cells. Our results showed that disruption of MAD2-p31{sup comet} axis by MAD2 knockdown or p31{sup comet} overexpression suppressed cell proliferation, survival and migration of glioma, indicating that MAD2-p31{sup comet} axis is required for maintaining glioma cells malignancy. It is noted that MAD2 depletion or p31{sup comet} overexpression reduced the sensitivity of glioma cells to microtubule-interfering agents paclitaxel and vinblastine, providing clinical guidance for application of such drugs. Taken together, our findings suggest that MAD2-p31{sup comet} axis may serve as a potential therapeutic target for glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CDCA3 promotes cell proliferation by activating the NF-κB/cyclin D1 signaling pathway in colorectal cancer

Highlights: • CDCA3 is upregulated in CRC tissues and cell lines. • Knockdown of CDCA3 inhibits CRC progression in vitro. • CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. • Overexpression of CDCA3 upregulates the NF-κB- related gene Cyclin D1. Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF-κB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A novel heme oxygenase-1 splice variant, 14kDa HO-1, promotes cell proliferation and increases relative telomere length

Alternative splicing is a routine phenomenon which greatly increases the diversity of proteins in eukaryotic cells. In humans, most multi-exonic genes are alternatively spliced and their splice variants confer distinct functions. Heme oxygenase-1 (HO-1, 32 kDa) is an inducible stress responsive protein, which possesses multiple functions in many cellular processes. In the current study, we identified a novel alternative splice isoform of 14 kDa HO-1 generated through exclusion of exon 3, and it is highly expressed in immortalized cells. In contrast to nuclear accumulation of the full-length 32 kDa HO-1, the novel 14 kDa HO-1 isoform is retained in the cytoplasm under ultraviolet (UV) irradiation. Interestingly, the 14 kDa HO-1 is shown to promote cell proliferation and an increase in relative telomere lengths in vivo and in vitro. Thus, we are pioneer to report and confirm the presence of a novel splice form of HO-1 and its distinct role in modulating telomere length and tumor growth.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

STAT3 activation by IL-6 from adipose-derived stem cells promotes endometrial carcinoma proliferation and metastasis

Endometrial cancer is the most common gynaecological cancer, and its incidence is increasing. Obesity is a well-recognized risk factor for endometrial cancer, and the mechanisms by which adipose tissue influences tumour development remain controversial. In this study, we examined the high IL-6 level in the ADSCs supernatant following treatment of endometrial cancer cell CM. Then, the activation of STAT3, a major tumourigenic IL-6 effector, was examined in ADSCs CM treated endometrial cancer cells. Conditioned ADSC medium was used to stimulate endometrial cancer cell growth in vitro. Similar to IL-6, ADSC-conditioned medium significantly promoted endometrial cancer growth and invasion. Furthermore, siRNA-mediated STAT3 inhibition in endometrial cancer cells decreased the ADSC-mediated promotion of cell proliferation and invasion. In addition, a subcutaneous nude mouse model of endometrial cancer was established to monitor the tumour-promoting effect of ADSCs. ADSC-conditioned medium promoted tumour growth, and STAT3 inhibition attenuated this effect. Based on these data, ADSCs promote endometrial cancer progression by the STAT3 signalling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CBX3 promotes proliferation and regulates glycolysis via suppressing FBP1 in pancreatic cancer

More and more evidence has demonstrated that Chromobox protein homolog 3(CBX3) has an important role in carcinogenesis by regulating several mechanisms, such as heterochromatin formation, gene silencing, DNA replication and repair. However, its role in pancreatic cancer has seldom been discussed. In the present study, we silenced CBX3 expression in pancreatic cancer cell lines and identified the positive roles of CBX3 in cancer cell proliferation. Furthermore, we demonstrated that silencing CBX3 in pancreatic cancer cells inhibited aerobic glycolysis, the basis for providing cancer cells with building blocks for macromolecule synthesis and ATP that required. To search for the underlying molecular mechanism, we turned to examine the impact of CBX3 on the expression of FBP1, a negative regulator of aerobic glycolysis in pancreatic cancer and indicated that CBX3 negatively regulated FBP1 expression. Silencing FBP1 expression attenuated the decrease in glycolytic capacity that caused by CBX3 knockdown in pancreatic cancer cells. Taken together, these data reveal that CBX3 serves as a positive regulator of aerobic glycolysis via suppressing of the FBP1 in pancreatic cancer cells. Disrupting the CBX3-FBP1 signaling axis would be effective to treat pancreatic cancer and prevent aerobic glycolysis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA hsa{sub c}irc{sub 0}008039 promotes breast cancer cell proliferation and migration by regulating miR-432-5p/E2F3 axis

As the development of sequencing technology, more and more circular RNAs (circRNAs) are identified in human cancer tissues. Increasing evidences imply circRNAs are important regulators in tumor progression. Nevertheless, how circRNAs participate in breast cancer development and progression is not well understood. In the present study, we identified a novel circRNA hsa{sub c}irc{sub 0}008039 with upregulated expression level in breast cancer tissues. By functional experiments, we found that hsa{sub c}irc{sub 0}008039 depletion significantly suppressed the proliferation, arrested cell-cycle progression and reduced migration in breast cancer. Mechanistic investigations suggested that hsa{sub c}irc{sub 0}008039 served as a competing endogenous RNA (ceRNA) of miR-432-5p. Subsequently, E2F3 was identified as the functional target of miR-432-5p and overexpression of hsa{sub c}irc{sub 0}008039 elevated E2F3 expression in breast cancer. On the whole, our study indicated that hsa{sub c}irc{sub 0}008039 exerted oncogenic roles in breast cancer and suggested the hsa{sub c}irc{sub 0}008039/miR-432-5p/E2F3 axis might be a potential therapeutic target.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Suppression of cleavage factor Im 25 promotes the proliferation of lung cancer cells through alternative polyadenylation

Non-small cell lung cancer (NSCLC) is a life-threatening disease that has a poor prognosis and low survival rate. Cleavage factor Im 25 (CFIm25) is a RNA-binding protein that if down-regulated causes 3′UTR shortening and thus promotes the transcript stability of target genes. It is not clear whether CFIm25 and alternative polyadenylation (APA) play a role during cancer development. The purpose of this study is to explore the role of CFIm25 in lung cancer cell proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Downregulation of hsa{sub c}irc{sub 0}007534 suppresses breast cancer cell proliferation and invasion by targeting miR-593/MUC19 signal pathway

Highlights: • We reported circular RNA, has{sub c}irc{sub 0}007534 in breast cancer (BC). • We reported mircro-RNA, miR-593 in breast cancer. • Has{sub c}irc{sub 0}007534 sponges miR-593 in BC. • MiR-593 directly targets MUC19 in BC. • Has{sub c}irc{sub 0}007534/miR-593/MUC19 axis plays critical role in BC pathogenesis. Circular RNAs (circRNAs) are important non-coding RNAs that are reportedly involved in the progression of diverse human cancers through their action as a microRNA (miRNA) sponge. However, the exact roles of circRNAs in breast cancer (BC) remain largely unknown. The present data demonstrate the significantly upregulated expression of hsa{sub c}irc{sub 0}007534 circRNA in BC tissues and cell lines. In contrast, miR-593 expression was significantly downregulated. Knockdown of hsa{sub c}irc{sub 0}007534 inhibited BC cell proliferation, colony formation, and invasion, and promoted apoptosis in BC cells. Moreover, hsa{sub c}irc{sub 0}007534 was demonstrated to be a sponge of miR-593, and expression of miR-593 in BC cells was negatively correlated with hsa{sub c}irc{sub 0}007534. MUC19 expression was markedly increased in BC tissues and cell lines, and the 3-UTR of MUC19 was targeted by miR-593. The expression of MUC19 was negatively regulated by miR-593 in BC cells. Our findings suggest an oncogenic role for hsa{sub c}irc{sub 0}007534 in BC by acting as a miR-593 sponge to promote MUC19 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

IL-13 and IL-13Rα1 are overexpressed in extranodal natural killer/T cell lymphoma and mediate tumor cell proliferation

Extranodal NK/T cell lymphoma (NKTCL) is a rare but aggressive subtype of non-Hodgkin lymphoma. Multi-agent chemotherapy and involved-field radiotherapy are used to treat this disease, but the prognosis remains poor. Interleukin 13 and its receptors (IL-13Rs) are correlated with the pathogenesis and progression of various malignances. However, their roles in NKTCL have not been evaluated. In this study, we examined the roles of IL-13 and IL-13Rs in NKTCL and the underlying mechanisms. We found significantly higher serum IL-13 levels (p < 0.001) and IL-13Rα1 expression in tumor tissues (36 of 40, p < 0.001) in patients with NKTCL than in control cohort. IL-13 secretion was observed in tumor tissues (30 of 40, p < 0.001) and several cell lines of NKTCL. However, we did not detect significant associations between clinical characteristics and the expression levels of IL-13 or IL-13Rs. In vitro, IL-13 activated Stat6 and promoted cell proliferation in a dose-dependent manner. In addition, blocking IL-13 exerted a negative effect on tumor cell growth. We conclude that IL-13 functions as an autocrine growth factor in NKTCL and contributes to its pathogenesis. Blocking IL-13 is thus a potential therapeutic approach for NKTCL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Activin A induces leiomyoma cell proliferation, extracellular matrix (ECM) accumulation and myofibroblastic transformation of myometrial cells via p38 MAPK

Highlights: • Activin A induces accumulation of ECM via the activation of p38 MAPK in HuLM cells. • Activation of p38 MAPK stimulates accumulation of ECM in HuLM cells. • SB202190 attenuates cell proliferation induced by Activin A via inhibit the activation of p38 MAPK in HuLM cells. • SB202190 attenuates deposition of ECM induced by Activin A via inhibit the activation of p38 MAPK in HM cells. • SB202190 interrupts myofibroblast differentiation and functional transformation of mice myometrial cells. The objective of this study was to evaluate the role of Activin A and p38β MAPK-activated signaling in human leiomyoma cells, myometrial cells and mouse myometrial tissues.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-125b-5p inhibits breast cancer cell proliferation, migration and invasion by targeting KIAA1522

Highlights: • miR-125b-5p expression was found downregulated in breast cancer. • We explored the tumor suppressive role of miR-125b-5p in breast cancer. • KIAA1522 was reported to function as oncogene in breast cancer. • KIAA1522 was a direct target of miR-125b-5p in breast cancer. Abnormal gene expression due to the dysregulation of microRNAs (miRNAs) often occurred in the initiation or progression of cancers. The aim of this present study was to investigate the function role of miR-125b-5p in breast cancer (BC). Expression levels of miR-125b-5p were determined by quantitative Real-time PCR. Biological functions of miR-125b-5p in the progression of BC were investigated with a series of in vitro experiments including cell counting kit-8 assay, colony formation assay, wound-healing assay and transwell invasion assay. The target of miR-125b-5p in BC was validated by luciferase activity reporter assay and western blot assay. We found miR-125b-5p expression was significantly reduced in BC cell lines compared to the normal breast epithelial cell line. Functional assays showed that cell proliferation, colony formation ability, cell migration, and cell invasion can be suppressed by miR-125b-5p overexpression. Besides, KIAA1522 was validated as a direct target of miR-125b-5p in BC. Collectively, our study showed that miR-125b-5p functions as a tumor suppressor and regulates BC progression through targeting KIAA1522.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hsa{sub c}ircRNA{sub 1}03809 regulated the cell proliferation and migration in colorectal cancer via miR-532–3p / FOXO4 axis

Highlights: • The expression of hsa{sub c}ircRNA{sub 1}03809 is down-regulated in the CRC tissues and cells. • Knockdown of hsa{sub c}ircRNA{sub 1}03809 promotes cell proliferation in CRC. • Knockdown of hsa{sub c}ircRNA{sub 1}03809 promotes cell migration in CRC. • Hsa{sub c}ircRNA{sub 1}03809 acts as a suppressor via regulation of miR-532–3P/FOXO4 axis in CRC. Circular RNAs(circRNAs) are a class of non-coding RNAs that are widely expressed in a variety of cell species. The role they play in cancers is poorly understood, especially in colorectal cancer (CRC). Hsa{sub c}ircRNA{sub 1}03809 (hsa{sub c}irc{sub 0}072088, circZFR)has been demonstrated to be lowly expressed in colorectal cancer tissues and is associated with stage and lymph node metastasis of cancer tissues. Real-time quantitative PCR (qRT-PCR) was used to verify the relationship of hsa{sub c}ircRNA{sub 1}03809 between colorectal cancer and paired adjacent tissue in clinical tissue samples. Then, the proliferative capacity, migration ability, cell cycle, and apoptosis were measured using wound-healing assay, CCK8, transwell assay, flow cytometry, and the like, when hsa{sub c}ircRNA{sub 1}03809 expression in SW620 and COCA-2. The qRT-PCR, western bolt and other experiments verify that the expression of hsa{sub c}ircRNA{sub 1}03809 can regulate the expression of miR-532–3P and FOXO4. Hsa{sub c}ircRNA{sub 1}03809 was found to be significantly down regulated in CRC tissues and cell lines and compared with paired adjacent non-tumorous tissues and normal FHC cells. Hsa{sub c}ircRNA{sub 1}03809 participates in the regulation of biological functions through the miR-532–3P/FOXO4 axis in the CRC. Hsa{sub c}ircRNA{sub 1}03809 may be a potential novel gene target for the diagnosis and treatment of CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen treatment facilitates cell proliferation and slowing down of DNA damage response in GST-P-expressing preneoplastic lesions

We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive {sup (+)} proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P{sup +} foci, compared with GST-P{sup +} foci expressing UBE2E2. However, p21{sup WAF1/CIP1}, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA{sup +} cells and γH2AX{sup +} cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P{sup +} foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P{sup +} foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90 days. Hepatocarcinogen treatment for 28 or 90 days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA{sup +} or γH2AX{sup +} cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P{sup +} proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis. - Highlights: • UBE2E2 downregulation was limited in GST-P-linked hepatocarcinogenesis. • UBE2E2 downregulation may stabilize c-MYC, KDM4A and KMT5A in GST-P{sup +} foci. • c-MYC and KMT5A may facilitate PCNA-mediated cell proliferation in GST-P{sup +} foci. • KDM4A may be responsible for slowing down of DNA damage response in GST-P{sup +} foci. • UBE2E2 downregulation triggers and further promotes carcinogenic responses.

60 APPLIED LIFE SCIENCES↗