RNase III Drosha initiates microRNA (miRNA) maturation by cleaving a primary miRNA transcript and releasing a pre-miRNA with a 2 nt 3′ overhang. Dicer recognizes the 2 nt 3′ overhang structure to ...selectively process pre-miRNAs. Here, we find that, unlike prototypic pre-miRNAs (group I), group II pre-miRNAs acquire a shorter (1 nt) 3′ overhang from Drosha processing and therefore require a 3′-end mono-uridylation for Dicer processing. The majority of let-7 and miR-105 belong to group II. We identify TUT7/ZCCHC6, TUT4/ZCCHC11, and TUT2/PAPD4/GLD2 as the terminal uridylyl transferases responsible for pre-miRNA mono-uridylation. The TUTs act specifically on dsRNAs with a 1 nt 3′ overhang, thereby creating a 2 nt 3′ overhang. Depletion of TUTs reduces let-7 levels and disrupts let-7 function. Although the let-7 suppressor, Lin28, induces inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in somatic cells lacking Lin28 to promote let-7 biogenesis. Our study reveals functional duality of uridylation and introduces TUT7/4/2 as components of the miRNA biogenesis pathway.
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▸ Unlike canonical group I miRNA precursors, group II members have a 1 nt 3′ overhang ▸ Mono-uridylation of group II pre-let-7 promotes Dicer processing ▸ TUT7, TUT4, and TUT2 catalyze pre-let-7 mono-uridylation in cells lacking Lin28 ▸ Lin28 induces oligo-uridylation to inhibit let-7 processing
Group II precursors require mono-uridylation by TUTases to create the overhang of 2 nt required for Dicer processing. In the presence of Lin28, let-7 is preferably oligo-uridylated by TUT4 promoting its degradation, revealing the functional duality of uridylation.
Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty ...liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.
•Correlations among micro-(1–5mm), meso-(5–25mm), and macro-(>25mm) plastic debris on beaches were tested.•The abundance of microplastics was strongly correlated with the abundance of mesoplastics, ...but not macroplastics.•Most of the microplastics were fragments of Styrofoam buoys from adjacent oyster culture facilities.•Mesoplastic surveys could be used to identify microplastic hot spots.
Plastic debris on six beaches near the Nakdong River Estuary, South Korea, was sampled in May and September 2012 and classified into three size classes, large microplastics (1–5mm), mesoplastics (5–25mm), and macroplastics (>25mm). The relationships among the abundances of the size classes were then examined. The abundances of each size category in May (before rainy season) and in September (after rainy season) were 8205 and 27,606particles/m2 for large microplastics, 238 and 237particles/m2 for mesoplastics, and 0.97 and 1.03particles/m2 for macroplastics, respectively. Styrofoam was the most abundant item both in microplastic and mesoplastic debris, while intact plastics were most common in macroplastic debris. The abundances of meso- and micro-plastics were the most strongly correlated. There was a higher correlation between the abundances of macro- and meso-plastics than between macro- and micro-plastics.
Hepatocellular carcinoma (HCC) is the second most common cancer worldwide, demonstrating aggressiveness and mortality more frequently in men than in women. Despite reports regarding the inhibitory ...ability of estrogen receptor alpha (ERα, ESR1) in certain cancer progression, targets and the basis of underlying gender disparity in HCC worsening remain elusive. Here, we report the ability of ERα to transcriptionally inhibit G protein subunit alpha 12 (Gα12) responsible for HCC worsening. First, using human samples and public database, the expression of ERα and Gα12 in HCC was examined. Then, quantitative real‐time PCR, chromatin immunoprecipitation‐assay, luciferase assay and immunoblottings of liver cancer cell lines confirmed the inhibitory ability of ERα on Gα12 and HCC progression. Gα12 promoted mesenchymal characteristics and amoeboidal movement, which was antagonized by ERα overexpression. Additionally, we found microRNA‐141 and microRNA‐200a as downstream targets of the Gα12 signaling axis for cancer malignancy regulation under the control of ERα. As for in‐depth mechanism, PTP4A1 was found to be directly inhibited by microRNA‐141 and microRNA‐200a. Moreover, we found the inhibitory effect of ERα on amoeboidal movement by analyzing the morphology and blebbing of liver cancer cells and the active form of MLC levels. The identified targets and ESR1 levels are inversely correlated with human specimens, as well as with sex‐biased survival rates of HCC patients. Collectively, ERα‐dependent repression of Gα12 and consequent changes in the Gα12 signaling may explain the gender disparity in HCC, providing pharmacological clues for the control of metastatic HCC.
What's new?
There is accumulating evidence that the incidence of hepatocellular carcinoma in males is higher than in females. Although ERα, a nuclear receptor of estrogen, plays a protective role in hepatocellular carcinoma progression, the underlying molecular mechanisms remain unclear. Here, the authors show that Gα12, a new inhibitory target of ERα, is increased in metastatic hepatocellular carcinoma and promotes the mesenchymal/amoeboid cell phenotype. The results of our study link the ERα‐Gα12 axis to gender‐biased hepatocellular carcinoma progression and could potentially pave the way for novel gender‐specific approaches in hepatocellular carcinoma treatment.
As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of ...let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology.
Tanaka (CJ)-related products are well-accepted by consumers worldwide; thus, they generate huge amounts of waste (peel, pulp, and seed) through CJ processing. Although some CJ by-products (CJBs) are ...recycled, their use is limited owing to the limited understanding of their nutritional and economic value. The exposure to particulate matter (PM) increases the risk of respiratory diseases. In this study, we investigated the ameliorative effects of CJB extracts (100, 200 mg/kg/day, 7 days) on PM10-induced (10 mg/kg, intranasal, 6 h) lung damage in BALB/c mice. Cell type-specific signaling pathways are examined using the A549 (PM10, 200 μg/mL, 6 h) and RAW264.7 (LPS, 100 ng/mL, 6 h) cell lines. The CJB extracts significantly attenuated PM10-induced pulmonary damage and inflammatory cell infiltration in a mouse model. The essential protein markers in inflammatory signaling pathways, such as AKT, ERK, JNK, and NF-κB for PM10-induced phosphorylation, were dramatically reduced by CJB extract treatment in both the mouse and cell models. Furthermore, the CJB extracts reduced the production of reactive oxygen species and nitric oxide in a dose-dependent manner in the cells. Comprehensively, the CJB extracts were effective in reducing PM10-induced lung injuries by suppressing pulmonary inflammation, potentially due to their anti-inflammatory and antioxidant properties.
Activation of sterol regulatory element‐binding protein 1 (SREBP‐1), a master lipogenic transcription factor, is associated with cancer metabolism and metabolic disorders. Neddylation, the process of ...adding NEDD8 to its substrate, contributes to diverse biological processes. Here, we identified SREBP‐1 as a substrate for neddylation by UBC12 and explored its impact on tumor aggressiveness. In cell‐based assays, SREBP‐1 neddylation prolonged SREBP‐1 stability with a decrease in ubiquitination. Consequently, NEDD8 overexpression facilitated proliferation, migration, and invasion of SK‐Hep1 liver tumor cells. MLN4924 (an inhibitor of the NEDD8‐activating enzyme‐E1) treatment or UBC12 knockdown prevented SREBP‐1 neddylation and tumor cell phenotype change. This effect was corroborated in an in vivo xenograft model. In human specimens, SREBP‐1, UBC12, and NEDD8 were all upregulated in hepatocellular carcinoma (HCC) compared to nontumorous regions. Moreover, SREBP‐1 levels positively correlated with UBC12. In GEO database analyses, SREBP‐1 levels were greater in metastatic HCC samples accompanying UBC12 upregulation. In HCC analysis, tumoral SREBP‐1 and UBC12 levels discriminated overall patient survival rates. Additionally, MLN4924 treatment destabilized SREBP‐1 in MDA‐MB‐231 breast cancer cells and in the tumor cell xenograft. SREBP‐1 and UBC12 were also highly expressed in human breast cancer tissues. Moreover, most breast cancers with lymph node metastasis displayed predominant SREBP‐1 and UBC12 expressions, which compromised overall patient survival rates. In summary, SREBP‐1 is neddylated by UBC12, which may contribute to HCC and breast cancer aggressiveness through SREBP‐1 stabilization, and these events can be intervented by MLN4924 therapy. Our findings may also provide potential reliable prognostic markers for tumor metastasis.
What's new?
The transcription factor sterol regulatory element‐binding protein‐1 (SREBP‐1) serves a key role in lipogenesis and is overexpressed in several cancer types. Its impact on cancer malignancy, however, remains unclear. This study identifies SREBP‐1 as a substrate for neddylation by UBC12, a NEDD8‐conjugating enzyme. Neddylation stabilized SREBP‐1, which was accompanied by decreased ubiquitination. Moreover, levels of SREBP‐1 and UBC12 were significantly elevated in metastatic human hepatocellular carcinoma (HCC) and breast cancer specimens and were further associated with patient survival. The findings suggest that increases of SREBP‐1 and UBC12 contribute to aggressive characteristics and overall progression of HCC and breast cancer.
We report the identification of novel highly pathogenic avian influenza viruses of subtype H5N6, clade 2.3.4.4, that presumably originated from China. In addition, reassortant strains with Eurasian ...lineage low pathogenic avian influenza viruses were isolated in wild birds and poultry in South Korea. The emergence of these novel H5N6 viruses and their circulation among bird populations are of great concern because of the potential for virus dissemination with intercontinental wild bird migration.
•Novel highly pathogenic avian influenza viruses of subtype H5N6 were detected in South Korea in 2016.•The Korean H5N6 viruses seem to be likely originated from H5N6 viruses circulating in Guangdong province of China.•Their reassortants with Eurasian lineage low pathogenic avian influenza viruses were isolated in wild birds and poultry.
Various approaches are required to prevent and treat heterogeneity-based prostate cancer. Here, we analyzed the anticancer effects of metformin, which has a good toxicity profile and is inexpensive.
...From January 2010 to December 2019, analysis was conducted retrospectively in a cohort from the National Health Insurance Service database. The wash-out period was set for cancer diagnosis in 2010 and 2011, and subjects (105,279) diagnosed with prostate cancer (ICD C61) from 2012 to 2014 were excluded The final subjects (105,216) were defined as the metformin administration group when they took metformin for 180 days or more from January 2012 to December 2019. The non-metformin group was defined as those who took less than 180 days from January 2012 to December 2019. The prevalence of prostate cancer according to metformin administration and the risk according to the cumulative duration of metformin were analyzed.
A total of 105,216 people were included in this study, with 59,844 in the metformin group and 45,372 in the metformin non-administration group. When calculating HRs (Hazard Rate) according to the cumulative period of metformin administration, metformin administration period length was inversely associated with prostate cancer risk (Q2 HR = 0.791 95% CI: 0.773-0.81, Q3 HR = 0.634 95% CI: 0.62-0.649, Q4 HR = 0.571 95% CI: 0.558-0.585). HRs tended to decrease with the cumulative duration of metformin administration.
This study confirmed that prostate cancer risk decreased with increasing duration of metformin administration. Metformin should be considered as a new strategy in the treatment and prevention of prostate cancer characterized by heterogeneity.
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