Relationship between HuR and tumor drug resistance

Human resistance protein R (HuR), also known as embryonic lethal abnormal visual-like protein (ELAVL1), is an RNA-binding protein widely expressed in vivo that affects the mRNA stability of targeted and is involved in post-transcriptional regulation. Recent studies have shown that HuR is aberrantly expressed in different human cancers and is an essential factor in poor clinical prognosis. The role of HuR in numerous tumors suggests that it could be a new target for tumor therapy and as a marker for efficacy and prognostic assessment. This review focuses on the relationship between HuR and drug resistance in different tumors and briefly describes the structure, function, and inhibitors of HuR. We summarize the mechanisms by which HuR causes tumor resistance and the molecular targets affected (AU)

Stable Lanthanide-Organic Frameworks: Crystal Structure, Photoluminescence, and Chemical Sensing of Vanillylmandelic Acid as a Biomarker of Pheochromocytoma.

Several isostructural lanthanide metal-organic frameworks, viz. [Ln(DCHB)1.5phen]n (Ln-MOFs, where Ln = Eu for 1, Tb for 2, Sm for 3 and Dy for 4), are successfully synthesized through the hydrothermal reactions of 4'-di(4-carboxylphenoxy)hydroxyl-2, 2'-bipyridyl (H2DCHB) and lanthanide nitrates as well as chelator 1,10-phenantroline (phen). These structures are characterized by single-crystal X-ray diffraction, and the representative Ln-MOF 1 is a fivefold interpenetrated framework with the uncoordinated Lewis base N sites form DCHB2- ligands. The photoluminescence research studies reveal that Ln-MOFs 1-4 exhibit characteristic fluorescent emissions from ligand-induced lanthanide Ln(III) ions, while the single-component emission spectra of Ln-MOF 4 are all located in a white region under different excitations. The absence of coordinated water and the interpenetration property of the structures are conducive to the structure rigidity, and the results display that Ln-MOF 1 has high thermal/chemical stabilities in common solvents and a wide pH range as well as the boiling water. Notably, luminescent sensing studies reveal that Ln-MOF 1 with prominent fluorescence properties can perform in highly sensitive and selective sensing of vanillylmandelic acid (VMA) in aqueous systems (KSV = 562.8 L·mol-1; LOD = 4.6 × 10-4 M), which can potentially establish a detection platform for the diagnosis of pheochromocytoma via multiquenching mechanisms. Moreover, the 1@MMMs sensing membranes comprised of Ln-MOF 1 and a poly(vinylidene fluoride) (PVDF) polymer can also be facilely developed for VMA detection in aqueous media, suggesting the enhanced convenience and efficiency of practical sensing applications.

Relationship between HuR and tumor drug resistance.

Human resistance protein R (HuR), also known as embryonic lethal abnormal visual-like protein (ELAVL1), is an RNA-binding protein widely expressed in vivo that affects the mRNA stability of targeted and is involved in post-transcriptional regulation. Recent studies have shown that HuR is aberrantly expressed in different human cancers and is an essential factor in poor clinical prognosis. The role of HuR in numerous tumors suggests that it could be a new target for tumor therapy and as a marker for efficacy and prognostic assessment. This review focuses on the relationship between HuR and drug resistance in different tumors and briefly describes the structure, function, and inhibitors of HuR. We summarize the mechanisms by which HuR causes tumor resistance and the molecular targets affected.

UCHL3 promotes hepatocellular carcinoma cell migration by de-ubiquitinating and stabilizing Vimentin.

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor associated with a poor prognosis. Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) has been reported to promote diverse tumors, but little is known about its role in HCC. Methods: Expression levels of UCHL3 in Huh7 and Hep3B cells were measured by qRT-PCR. UCHL3, Vimentin protein levels, and ubiquitination levels were determined by Western blot assay. co-immunoprecipitation, Immunofluorescence, and IHC were used to detect the interaction and expression association between UCHL3 and Vimentin in the cells. Wound healing and Transwell assays were used to measure cell migration. Spheroid formation assay were used to assess stem-like properties. Results: UCHL3 expression was found to be significantly elevated in HCC and associated with poor prognosis. UCHL3 promoted migration and stem-like properties of HCC cells. Vimentin was identified as a potential de-ubiquitination substrate of UCHL3 and UCHL3 interacted with and promoted the de-ubiquitination of Vimentin, enhancing its stability. Moreover, the suppression of UCHL3 by siRNA or the inhibition by TCID upregulated ubiquitinated Vimentin. Vimentin attenuated the suppression of cell migration caused by knockdown of UCHL3. Conclusion: UCHL3 was highly expressed in HCC and functioned as an oncogene. Vimentin is a novel substrate of UCHL3 and its stabilization and de-ubiquitination enhanced HCC cell migration.

LncRNA FRMD6-AS1 promotes hepatocellular carcinoma cell migration and stemness by regulating SENP1/HIF-1α axis.

BACKGROUND: Long non-cording RNAs (lncRNAs) drive the malignant progression of hepatocellular carcinoma (HCC), a cancer with high mortality rates but the function of FERM Domain Containing 6 antisense RNA 1 (FRMD6-AS1) in HCC has not been fully addressed. Hypoxia-inducible factors (HIFs) are transcription factors relevant to HCC under hypoxia and are regulated by SUMO-specific protease 1 (SENP1) through its deSUMOylation of HIF-1α. The current study investigated the role of FRMD6-AS1 in the regulation of SENP1-mediated deSUMOylation of HIF-1α. METHODS: HUH7 and MHCC97H cells were treated with CoCl2 to mimic hypoxia in vitro and lentiviral vector-mediated FRMD6-AS1 overexpressing HCC cells were established. Wound-healing, Transwell, sphere formation assay, Western blotting analysis and animal experiments were performed. Expression of FRMD6-AS1, SENP1 mRNA and HIF-1α mRNA was assessed by RT-qPCR and of HIF-1α and SENP1 protein by Western blot. DeSUMOylation of HIF-1α was detected by immunoprecipitation. RNA immunoprecipitation with SENP1 antibody or IgG was performed to assess endogenous interactions between SENP1 and FRMD6-AS1. RESULTS: FRMD6-AS1 was upregulated in HCC tissues and cells and its upregulation indicated poor prognosis for HCC patients. FRMD6-AS1 promoted HCC cells migration and stemness in vitro and also promoted tumor growth in an in vivo mouse xenograft model. Mechanistic studies showed that FRMD6-AS1 regulated the level of HIF-1α protein but not the mRNA and this effect was achieved by binding to SENP1 protein and enhancing its protease activity. Rescue experiments demonstrated the oncogenic role of the FRMD6-AS1/SENP1/ HIF-1α axis in HCC cells. CONCLUSIONS: High FRMD6-AS1 expression was associated with poor prognosis of HCC patients. FRMD6-AS1 may have an oncogenic role in HCC via regulation of the SENP1/HIF-1α axis and may be a prognostic biomarker for HCC. Blockade of FRMD6-AS1 may offer a novel therapeutic approach to restrict HCC progression.

Ubiquitin­conjugating enzymes as potential biomarkers and therapeutic targets for digestive system cancers (Review).

Digestive system cancers are the leading cause of cancer­related death worldwide due to their high morbidity and mortality rates. The current treatment methods include surgical treatment, chemotherapy, radiotherapy and endoscopic treatment, and the precisely targeted therapy of digestive system cancers requires to be further studied. The ubiquitin­proteasome system is the main pathway for protein degradation in cells and the ubiquitin­conjugating enzymes (E2s) have a decisive role in the specific selection of target proteins for degradation. The E2s have an important physiological role in digestive system cancers, which is related to the clinical tumor stage, differentiation degree and poor prognosis. Furthermore, they are involved in the physiological processes of digestive system tumor cell proliferation, migration, invasion, stemness, drug resistance and autophagy. In the present article, the progress and achievements of the E2s in gastric cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer, intrahepatic cholangiocarcinoma, gallbladder cancer and esophageal squamous cell carcinoma were reviewed, which may provide early screening indicators and reliable therapeutic targets for digestive system cancers.

UBE2K promotes the malignant progression of hepatocellular carcinoma by regulating c-Myc.

Hepatocellular carcinoma (HCC) is a serious threat to human health and life due to its high morbidity and mortality. Ubiquitin-conjugating enzymes are players in the ubiquitin proteasome system and are responsible for a great number of physiological activities in cells. The action of ubiquitin-conjugating enzyme UBE2K in HCC has not been reported. Therefore, we studied the function and role of UBE2K in the malignant progression of HCC. An analysis of UBE2K expression in HCC cells was performed using RT-qPCR and protein immunoblotting. CCK-8, Transwell and sphere formation assays were used to identify the potential effects of UBE2K in HCC cell proliferation, migration and stemness property. RT-qPCR, and protein immunoblotting experiments was taken to explore the regulation between UBE2K and c-Myc. Here, we discovered that UBE2K expression was elevated in HCC cells, and elevated UBE2K predicts worse prognosis for HCC patients. Functionally, UBE2K promote, while UBE2K knockdown suppressed cell proliferation, migration and stemness property of HCC cells. Furthermore, c-Myc was identified as a downstream target of UBE2K. Moreover, functional rescue experiments finally proved that UBE2K facilitates the malignant progression of HCC cells by upregulating c-Myc. We clarified through in vivo experiments that UBE2K expression promotes tumor growth in HCC. Taken together, our study results proved the molecular regulation of UBE2K and c-Myc in HCC and the oncogenic role of UBE2K/c-Myc axis in HCC progression, thus it provides a promising molecular target for the diagnosis and treatment of HCC.

LncRNA ALKBH3-AS1 enhances ALKBH3 mRNA stability to promote hepatocellular carcinoma cell proliferation and invasion.

Long noncoding RNAs (lncRNAs) are confirmed as the key regulators of hepatocellular carcinoma (HCC) occurrence and progression, but the role of AlkB homologue 3 antisense RNA 1 (ALKBH3-AS1) in HCC is unclear. We revealed the overexpression of ALKBH3-AS1 in HCC tissues. The upregulated levels of ALKBH3-AS1 were observed in HCC cells. ALKBH3-AS1 was expressed in the nucleus and cytoplasm of HCC cells. The high ALKBH3-AS1 expression was markedly associated with a decreased survival rate of HCC patients. ALKBH3-AS1 knockdown repressed and ALKBH3-AS1 overexpression enhanced HCC cell invasion and proliferation. ALKBH3-AS1 silencing restricted HCC growth in vivo. A significant positive correlation between ALKBH3-AS1 and ALKBH3 mRNA levels was confirmed in HCC specimens. ALKBH3-AS1 silencing reduced ALKBH3 expression by stabilizing its mRNA stability in HCC cells. Notably, the impact of ALKBH3 silencing on HCC cells was similar to that of ALKBH3-AS1 knockdown. ALKBH3 restoration prominently attenuated the suppressive effects resulting from ALKBH3-AS1 silencing in HCCLM3 cells. Hypoxia-inducible factor-1α (HIF-1α) transcriptionally activated ALKBH3-AS1 expression in hypoxic HCC cells. ALKBH3-AS1 knockdown markedly attenuated cell proliferation and invasion in hypoxic Huh7 cells. Collectively, HIF-1α-activated ALKBH3-AS1 exerted an oncogenic role by enhancing ALKBH3 mRNA stability in HCC cells.

Research Progress of DUB Enzyme in Hepatocellular Carcinoma.

According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.

Evaluating the direct medical cost, drug utilization and expenditure for managing Parkinson's disease: a costing study at a medical center in China.

Background: With long-term pharmacotherapy, Parkinson's disease (PD) is expectedly to incur a significant healthcare burden. However, drug utilization and costing study is limited, so is the cost composition and its impact on resource allocation. This study took a healthcare provider's perspective to quantify medical and drug expenses and the utilization of drugs for managing PD and its complications. Methods: Medical resources use and associated cost of outpatient visits and inpatient admission episodes for PD patients were extracted from electronic medical records at a tertiary hospital in China from 1 January 2016 to 15 August 2018. Total and average direct medical (costs of outpatient visits and inpatient admission episodes) and drug costs were calculated during the study period and each calendar year. Drug cost was quantified by defined daily dose cost (DDDc) and levodopa equivalent dose cost (LEDc) per outpatient visit or inpatient admission episode for PD in Chinese yuan (¥), stratified by medication categories, and presented in descriptive statistics. Results: Overall, 18,158 outpatient visits and 366 inpatient admissions were incurred by 2,640 outpatients and 330 inpatients, with a median age of 71.0 and 73.5 years, respectively. Drug cost accounted for 97.82% and 23.33% of outpatient and inpatient medical expenditure. The average cost of drugs for managing PD accounted for 60.48% (¥952.50) and 2.70% (¥564.90) of cost per outpatient visit and inpatient episode, while drugs for managing PD complications was 11.38% and 0.70%, respectively. The highest DDDc and LEDc of drugs for managing PD per outpatient visit or inpatient episode were incurred by pramipexole (¥56.90-72.70 and ¥227.48-290.67) and entacapone (¥37.70-45.70 and ¥228.64-276.77). The DDDc and LEDc of pramipexole is more than 10 times that of levodopa/benserazide (DDDc: ¥4.90-5.70; LEDc: ¥10.14-11.98) and carbidopa/levodopa (DDDc: ¥4.00-5.00; LEDc: ¥11.02-13.95). Conclusions: The outpatient direct medical cost for patients with PD was predominantly attributed to drug cost for managing PD, but drug cost weighed less of the inpatient cost. After adjusting the dose and number of patients, drugs with indirect dopamine effects had an excessively higher cost than dopamine precursors. Their long-term cost-effectiveness in real-world settings warrants further studies.

A novel dual-functional fluorescent probe for imaging viscosity and cysteine in living system.

Abnormal changes in intracellular viscosity and cysteine are both associated with several important biological processes such as reversible redox reactions, which play a pivotal role in the process of inflammation. However, it remains unclear how cysteine and viscosity are altered in inflammation. Herein, we firstly report a high-sensitivity and -selectivity near-infrared imaging probe (FCV) for tracking intracellular viscosity and endogenous cysteine. This dual-functional probe displays excellent photostability and large Stokes shifts. FCV exhibits a 54-fold enhancement in fluorescence emission at 560 nm with increasing Cys (λex = 420 nm) and an approximately 63-fold enhancement at 660 nm (λex = 460 nm) with increasing viscosity from 1.0 cP to 952.5 cP. Moreover, FCV reveals the synergistic relationship between viscosity and cysteine in the inflammation model of living cells and zebrafish for the first time. Thus, FCV is a promising vehicle to identify the changes in Cys and viscosity in associated diseases.

Line interference effects using a refined Robert-Bonamy formalism: the test case of the isotropic Raman spectra of autoperturbed N2.

A symmetrized version of the recently developed refined Robert-Bonamy formalism [Q. Ma, C. Boulet, and R. H. Tipping, J. Chem. Phys. 139, 034305 (2013)] is proposed. This model takes into account line coupling effects and hence allows the calculation of the off-diagonal elements of the relaxation matrix, without neglecting the rotational structure of the perturbing molecule. The formalism is applied to the isotropic Raman spectra of autoperturbed N2 for which a benchmark quantum relaxation matrix has recently been proposed. The consequences of the classical path approximation are carefully analyzed. Methods correcting for effects of inelasticity are considered. While in the right direction, these corrections appear to be too crude to provide off diagonal elements which would yield, via the sum rule, diagonal elements in good agreement with the quantum results. In order to overcome this difficulty, a re-normalization procedure is applied, which ensures that the off-diagonal elements do lead to the exact quantum diagonal elements. The agreement between the (re-normalized) semi-classical and quantum relaxation matrices is excellent, at least for the Raman spectra of N2, opening the way to the analysis of more complex molecular systems.

Line coupling effects in the isotropic Raman spectra of N2: a quantum calculation at room temperature.

We present quantum calculations of the relaxation matrix for the Q branch of N2 at room temperature using a recently proposed N2-N2 rigid rotor potential. Close coupling calculations were complemented by coupled states studies at high energies and provide about 10,200 two-body state-to state cross sections from which the needed one-body cross-sections may be obtained. For such temperatures, convergence has to be thoroughly analyzed since such conditions are close to the limit of current computational feasibility. This has been done using complementary calculations based on the energy corrected sudden formalism. Agreement of these quantum predictions with experimental data is good, but the main goal of this work is to provide a benchmark relaxation matrix for testing more approximate methods which remain of a great utility for complex molecular systems at room (and higher) temperatures.