LncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis in gastric cancer by targeting miR-605-3p.

The article "LncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis in gastric cancer by targeting miR-605-3p", by Y.-Z. Su, M.-F. Cui, J. Du, B. Song, published in Eur Rev Med Pharmacol Sci 2020; 24 (3): 1158-1167-DOI: 10.26355/eurrev_202002_20167-PMID: 32096164, has been retracted by the authors since some experiment reagent in this article might be questionable (that may influence the accuracy of the final results). The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20167.

LncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis in gastric cancer by targeting miR-605-3p.

OBJECTIVE: Gastric cancer (GC) is one of the most common cancers in the world, with a high incidence and a poor prognosis. A large number of lncRNAs have been demonstrated to play multiple important roles in cancer development and progression. LncRNA is usually used as ceRNA and forms a regulatory network with miRNA in gastric cancer. However, the function and regulatory network of lncRNA in gastric cancer have not been fully elucidated. MATERIALS AND METHODS: The qRT-PCR assay was used to detect DCST1-AS1 and miR-605-3p expression. Western blot was applied to measure the protein expression of CDK4, cyclin D1, MMP-2, MMP-9, cleaved caspase 3, Bcl-2, Bax and ß-actin. MTT assay and flow cytometry were performed to assess cell proliferation and apoptosis, respectively. Transwell migration and invasion assay were used to determine cell migration capacity and invasion ability. Luciferase reporter assay was applied to determine the relationship of DCST-AS1 and miR-605-3p in GC. RESULTS: In this study, we found that DCST1-AS1 was highly expressed while miR-605-3p was low expressed in GC tissues and cells. Moreover, DCST1-AS1 expression negatively regulated miR-605-3p expression in GC. Functionally test demonstrated that knockdown of DCST1 inhibited cell proliferation, migration and invasion as well as promoted cell apoptosis in GC cells. Interestingly, miR-605-3p has been verified to be a target miRNA of DCST1-AS1 with luciferase reporter assay. More than that, the reverse experiment determined that the inhibition of miR-605-3p could alleviate the suppressive effects of low DCST1-AS1 expression on cell growth in GC. CONCLUSIONS: We proved the regulatory network of lncRNA DCST1-AS1 for the first time, and also explored and found that lncRNA DCST1-AS1 regulated cell proliferation, migration, invasion and apoptosis by regulation of miR-605-3p, providing a new therapeutic target for gastric cancer treatment.

Effects of changes in serum endostatin and fibroblast growth factor 19 on the chemotherapeutic sensitivity in acute myeloid leukemia patients.

The present study aimed to explore the changes in serum endostatin and fibroblast growth factor 19 (FGF-19) in acute myeloid leukemia patients, and to determine their effects on chemotherapeutic sensitivity. Sixty acute myeloid leukemia patients and 30 healthy controls were included in the study. Patient serum endostatin and FGF-19 levels were measured on admission, and then, standard chemotherapy was administered. The patients were divided into 2 groups according to chemotherapeutic effects: 21 patients in the chemotherapeutic sensitivity group (complete remission + partial remission) and 39 in the chemotherapeutic resistance group (no remission + degradation). A receiver operating characteristic (ROC) curve was used to analyze the relationship of serum endostatin and FGF-19 levels with chemotherapeutic sensitivity in acute myeloid leukemia patients. The levels of serum endostatin and FGF-19 in acute myeloid leukemia patients before chemotherapy were significantly higher than those in the control group. Moreover, these levels significantly decreased after chemotherapy (P < 0.01). The levels of serum endostatin and FGF-19 in the chemotherapeutic sensitivity group were lower than those in the chemotherapeutic resistance group, both before and after chemotherapy (P < 0.05 and P < 0.01, respectively). ROC curve analysis showed that the predictive values of endostatin and FGF-19 were good, and there was no significant difference between these results. In conclusion, serum endostatin and FGF-19 can be used as predictors of chemotherapeutic sensitivity for acute myeloid leukemia patients, and may be important for determining prognosis.

Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy.

This study explored the clinical significance of silencer of death domain (SODD) expression in childhood acute lymphoblastic leukemia (ALL) and its influence on chemotherapy as well as the effect of SODD expression on apoptosis of leukemic cells. The expression of SODD proteins in different ALL groups was determined by immunocytochemistry. The SODD RNAi-interfering plasmid was constructed and transferred to Jurkat cells, and the effects of SODD expression on cell proliferation and apoptosis were analyzed using the MTT and FCM methods. The expressions of SODD, Phospho-NF-κB-P65, Bcl-2, and Caspase 3 were detected by Western blot analysis. The expression of SODD proteins was significantly higher in the ALL groups than in the control group (P < 0.05). The positive expression rate of SODD was significantly higher in refractory/relapsed and clinical high-risk groups than in standard-risk, initial treatment, and complete remission groups (P < 0.05). Microtubule-targeting drugs such as vincristine and taxol can notably down-regulate SODD expression during apoptosis, whereas DNR, and Ara-c cannot. The sensitivity of Jurkat cells to chemotherapeutic drugs increased with down-regulated SODD expression induced by SODD-interfering plasmid transfection. The sensitivity of the cells transfected with SODD-cloning genes decreased. SODD expression was high in the ALL children. These findings indicated that SODD over-expression might be correlated with the clinical classification, curative effect, and prognosis of ALL cells. Microtubule-targeting drugs can specifically down-regulate SODD expression in leukemic cells, thereby increasing the sensitivity of leukemic cells to SODD-targeting chemotherapeutics. In contrast, increased SODD expression tends to reduce sensitivity.

Update on diversity and distribution of HIV-1 subtypes in Yunnan province.

The aim of this study was to characterize updated HIV subtypes in Yunnan to determine their origins and distribution within the population. RT-PCR of both the gag and env genes were sequenced from Yunnan province inhabitants newly diagnosed with HIV-1. Sequence data from 290 samples were used for statistical analysis of subtype distribution and phylogenetic tree construction. Distribution data were adjusted to account for different geographical distributions of HIV-1 subtypes in the population. Phylogenetic analysis revealed six HIV-1 subtypes in Yunnan, including eight types of unique recombination forms (URFs). The most prevalent subtypes in this province, CRF07_BC (18·9%), CRF08_BC (39·1%), CRF01_AE (22·4%), and URFs (subtype C, 5·9% and subtype B, 4·5%), were all recombinants. We found significant differences in the distribution of these HIV-1 subtypes not only geographically, but also between various ethnic groups and with respect to transmission routes. Our findings indicate a complex population of HIV-1 subtypes, URFs, and recombinant subtypes in Yunnan province. This diversity could make the prevention and control of HIV infection in Yunnan more difficult due to the possibility of virus recombination or infection by multiple subtypes.

Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application.

Protein kinase C (PKC) is an enzyme involved in the regulation of cellular growth, proliferation, and differentiation in a number of tissues including the anterior pituitary, in which it is also believed to play a role in hormone secretion. Protein kinase C activity and expression have been found to be greater in adenomatous pituitary cells than in normal human and rat pituitary cells and higher in invasive pituitary tumor cells than in noninvasive ones. Inhibition of PKC activity has been shown in a variety of tumor cells to inhibit growth in a dose-related fashion. The purpose of the current study was to determine whether hypericin, a potent inhibitor of PKC activity that may be administered clinically, alters the growth and proliferation in established pituitary adenoma lines and to determine if inhibition of PKC activity induces apoptosis, as reported in some other tumor cell types. Two established pituitary adenoma cell lines, AtT-20 and GH4C1, were treated with hypericin in tissue culture for defined periods following passage. Inhibition of growth was found to be dose dependent in all three cell lines in low micromolar concentrations of hypericin, as determined by viable cell counts, methylthiotetrazole assay, and [3H]thymidine uptake studies. Concentrations of hypericin as low as 100 nM also induced apoptosis in these established lines, whereas treatment of normal human fibroblasts with a concentration of 10 microM failed to induce apoptosis. The potential use of hypericin in the therapy of pituitary adenomas warrants additional in vitro investigations with the aim of later moving toward therapeutic trials in selected patients in whom surgical or medical therapy has failed.

Distinct P-glycoprotein expression in two subclones simultaneously selected from a human colon carcinoma cell line by cis-diamminedichloroplatinum (II).

Two drug-resistant sublines, CP2.0 and RT, were simultaneously selected by cis-diamminedichloroplatinum (CDDP) from the human colon carcinoma cell line LoVo by the conventional method of continuous drug exposure. The 2 sublines differed in morphology, growth kinetics and pattern of gene expression. Genetic signature analysis indicated that the lines were independent subclones but that both arose from LoVo. These sublines were maintained in a growth medium containing 2.0 micrograms/ml CDDP. However, CP2.0 cells were 3 times more resistant to CDDP than were RT cells. Although both were cross-resistant to mustargen and 5-fluorouracil, only CP2.0 was resistant to Adriamycin and vincristine. Western-blot analysis, immunocytochemical staining and in vitro phosphorylation experiments indicated that the level of P-glycoprotein was significantly elevated in CP2.0 but not in RT. Despite the differences between these sublines, they possess similar CDDP-resistance mechanisms, including decreased intracellular CDDP accumulation, elevated levels of glutathione and metallothionein-like proteins, increased glutathione transferase-pi mRNA, and enhanced susceptibility to CDDP cytotoxicity after treatment with DL-buthionine-[S,R]-sulfoximine. Nevertheless, our results suggest that, in certain tumor types, P-glycoprotein-mediated multi-drug resistance and CDDP-resistance phenotypes can coexist in cells with primary resistance to CDDP.

2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms.

2-Chlorodeoxyadenosine (2-CDA) is an adenosine deaminase resistant analogue of deoxyadenosine which has shown clinical activity in human hematologic neoplasms. The exact mode of action of this drug remains the subject of investigation. We applied the Differential Staining Cytotoxicity (DiSC) assay to 50 human tumour specimens obtained from patients with a variety of hematologic malignancies to characterise the activity spectrum of 2-CDA. We evaluated the disease-specific activity of this agent in vitro and compared its relative cytotoxicity with that of other antineoplastic agents in current clinical use. Comparisons were conducted against nitrogen mustard, doxorubicin, vincristine and cytosine arabinoside. Our results indicate that 2-CDA has activity in myeloid and many lymphoid neoplasms but that multiple myeloma specimens reveal significant resistance. Cross resistance studies reveal a correlation between 2-CDA and the alkylator nitrogen mustard but no correlation between 2-CDA and doxorubicin, vincristine nor cytosine arabinoside. The results suggest 2-CDA activity in many human hematologic neoplasms with the clear exception of multiple myeloma and further suggest a relationship between this agent and alkylators of the mustard class. The DiSC assay may provide useful insights in the pre-clinical evaluation of new antineoplastic drugs and may help to elucidate drug activities and mechanisms of action.

Further characterization of two distinct adriamycin-resistant sublines from LoVo human colon carcinoma cells.

We previously reported that two multidrug resistant sublines, AdR1.2 and SRA1.2, derived from LoVo human colon carcinoma cells, apparently expressed different resistance phenotypes including differential expression of p-glycoprotein (Pgp). Here, we further examined and compared other potential resistance mechanisms between AdR1.2 and SRA1.2 resistant cells. Our results showed that the Pgp-mediated AdR1.2 cells possessed an activated drug efflux pump and decreased nucleus binding of Adriamycin, while the non-Pgp-mediated SRA1.2 cells only held the second feature. Verapamil, however, partially reversed resistance in both sublines. Although glutathione-s-transferase was overexpressed in AdR1.2 but not in SRA1.2, both sublines had lower susceptibilities to drug-induced DNA strand breaks and greater capacities to repair such damage than did LoVo cells. These data suggest that, despite the differences in multidrug resistance phenotypes, the features of decreased susceptibility to DNA damage and enhanced DNA repair capacities may represent the common mechanisms responsible for drug resistance in both Pgp- and non-Pgp-mediated multidrug resistant cells.

Heterogeneous effects of interferon on antitumor agents' cytotoxicities to human colon carcinoma cell lines.

Six established human colon carcinoma cell lines that segregated into three groups with different degrees of differentiation were treated using three subclasses of interferons as single agents and in combination with either 5-fluorouracil, cis-platinum, or adriamycin. The cytotoxicities of the combination treatments were heterogeneous and did not relate to the cell's levels of differentiation. Our data suggest that the optimal combinations of interferons and chemotherapeutic agents are independent of the differentiation state of the colon cancer cells.

Metronidazole enhances the cytotoxic synergism produced by the combination of 1-beta-arabinofuranosylcytosine and cis-diamminedichloroplatinum.

Metronidazole (MZ) was evaluated as a single agent or in combination with CDDP and araC for its cytotoxic effects on five established human colon carcinoma cell lines. MZ alone produced little cytotoxicity at 1 h drug incubation. The cytotoxicity was detectable only after 2 h incubation and increased as a function of duration of treatment, suggesting a time-dependent rather than a dose-dependent cytotoxic effect. MZ had no effect on CDDP- or araC-induced cytotoxicity, whereas MZ enhanced the synergism resulting from the combination of two antitumor agents on the human colon tumor cell lines tested. Such enhancement was more pronounced on cells growing in stationary rather than in exponential phase. MZ not only produced a reversible S-phase arrest but also lessened the CDDP-produced inhibition on the incorporation of araC into DNA. However, it did not enhance CDDP-induced DNA cross-linkings, with or without araC. Our results indicated that MZ enhanced the synergism produced by two antitumor drugs in combination and that enhancement was accompanied by an increase in S-phase population and of the incorporation of araC into nucleic acids.

Perturbation of in vitro drug resistance in human lymphatic neoplasms by combinations of putative inhibitors of protein kinase C.

Fresh specimens of human lymphatic neoplasms were tested with the differential staining cytotoxicity assay. Cells from relapsed patients with acute lymphoblastic leukemia (ALL) were significantly more resistant to vincristine, dexamethasone, and doxorubicin in the assay than were cells from previously untreated patients. The putative C kinase inhibitors verapamil (V), imipramine (I), lidocaine (L), tamoxifen (T), chlorpromazine (C), and haloperidol (H) were then tested singly, in combination with each other (VILTCH, ITCH, and VL), and in combination with vincristine. At concentrations judged to be clinically achievable, VILTCH itself was occasionally toxic to ALL and chronic lymphocytic leukemia. The VILTCH combination clearly potentiated the cytotoxic activity of vincristine in five of eight ALL specimens from relapsed patients and potentiated vincristine in 18 of 30 chronic lymphocytic leukemia specimens. It also potentiated vincristine in two of six specimens of multiple myeloma and five of six specimens of non-Hodgkin's lymphoma. The VILTCH combination had no significant effects in fresh cultures of normal human lymphocytes. The most active drugs in the VILTCH combination appeared to be verapamil and lidocaine. We conclude that the differential staining cytotoxicity assay is a useful tool to study the circumvention of clinically acquired drug resistance. While the mechanism of the observed enhancement of the cytotoxic effects of vincristine is not known, it is possible that combinations of putative C kinase inhibitors may reduce drug resistance in human lymphatic neoplasms.

Selective enhancement by menadiol of in vitro drug activity in human lymphatic neoplasms.

The effect of menadiol (vitamin K3) on fresh specimens of human lymphatic neoplasms (HLN) was tested by means of the differential staining cytotoxicity assay. Menadiol was tested alone and in combination with standard antineoplastic agents. Drug effects were then compared with the effects of the same drugs in normal human lymphocytes and in fresh specimens of human non-small cell lung cancer. By itself, menadiol was moderately toxic to HLN, but not to normal lymphocytes or non-small cell lung cancer. Menadiol, menadione, and two structurally related congeners were equitoxic to HLN cells, but sodium metabisulfite (present in menadiol solutions as a preservative) was nontoxic. Menadiol increased the cytotoxic effects of a number of standard agents in HLN but not in normal lymphocytes. Cell survival times with mechlorethamine, vincristine, and dexamethasone were converted from a range characteristic of drug resistance (ie, range observed in relapsed patients) to a range characteristic of drug sensitivity (ie, range observed in untreated patients) in the presence of menadiol. These effects occurred at a concentration (2.0 micrograms/ml; 4.7 microM) of menadiol which is probably clinically achievable and which did not deplete intracellular glutathione. Menadiol should receive clinical testing as a chemosensitizing agent in HLN.