Ligand-Mediated Magnetism-Conversion Nanoprobes for Activatable Ultra-High Field Magnetic Resonance Imaging.

Ultra-high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low-field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand-mediated magnetism-conversion nanoprobe (MCNP) composed of 3-mercaptopropionic acid ligand-coated silver-gadolinium bimetallic nanoparticles. The MCNP exhibits a pH-dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH-activatable UHF MRI. Under neutral pH, the thiolate (-S- ) ligands lead to short τ'm and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (-SH) ligands, resulting in prolonged τ'm and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH-sensitive changes in Ag-S binding affinity of the MCNP lead to a remarkable (>10-fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next-generation UHF-tailored smart MRI contrast agent.

An Immunomodulatory Zinc-Alum/Ovalbumin Nanovaccine Boosts Cancer Metalloimmunotherapy Through Erythrocyte-Assisted Cascade Immune Activation.

Cancer therapeutic vaccines are powerful tools for immune system activation and eliciting protective responses against tumors. However, their efficacy has often been hindered by weak and slow immune responses. Here, the authors introduce an immunization strategy employing senescent erythrocytes to facilitate the accumulation of immunomodulatory zinc-Alum/ovalbumin (ZAlum/OVA) nanovaccines within both the spleen and solid tumors by temporarily saturating liver macrophages. This approach sets the stage for boosted cancer metalloimmunotherapy through a cascade immune activation. The accumulation of ZAlum/OVA nanovaccines in the spleen substantially enhances autophagy-dependent antigen presentation in dendritic cells, rapidly initiating OVA-specific T-cell responses against solid tumors. Concurrently, ZAlum/OVA nanovaccines accumulated in the tumor microenvironment trigger immunogenic cell death, leading to the induction of individualized tumor-associated antigen-specific T cell responses and increased T cell infiltration. This erythrocyte-assisted cascade immune activation using ZAlum/OVA nanovaccines results in rapid and robust antitumor immunity induction, holding great potential for clinical cancer metalloimmunotherapy.

Alpha-Synuclein Oligomers Driven T1-T2 Switchable Nanoprobes for Early and Accurate Diagnosis of Parkinson's Disease.

The alpha-synuclein (α-syn) oligomers hold a central role in the pathology of Parkinson's disease (PD). Achieving accurate detection of α-syn oligomers in vivo presents a promising avenue for early and accurate diagnosis of PD. Magnetic resonance imaging (MRI), with non-invasion and exceptional tissue penetration, offers a potent tool for visualizing α-syn oligomers in vivo. Nonetheless, ensuring diagnostic specificity remains a formidable challenge. Herein, a novel MRI probe (ASOSN) is introduced, which encompasses highly sensitive antiferromagnetic nanoparticles functionalized with single-chain fragment variable antibodies, endowing it with the capacity for discerning recognition and binding to α-syn oligomers and triggering a switchable T1-T2 MRI signal. Significantly, ASOSN possesses the unique capability to accurately discriminate α-syn oligomers from neuroinflammation in vivo. Moreover, ASOSN facilitates the non-invasive and precise visualizing of endogenous α-syn oligomers in living systems. This innovative design heralds the development of a non-invasive visualization strategy for α-syn oligomers, marking a pivotal advancement for early and accurate diagnosis of PD.

A Cancer Cell Selective Replication Stress Nano Amplifier Promotes Replication Fork Catastrophe to Overcome Radioresistance.

Replication stress (RS) induced by DNA damage plays a significant role in conferring the anticancer effects of radiotherapy and is tightly associated with radioresistance of cancer cells. Amplification of RS represents an effective approach to improving the efficacy of radiotherapy, although the development of selective RS amplifiers remains an unexplored frontier. We herein present an RS nano amplifier (RSNA) consisting of a catalytic FePt nanoparticle loaded with the chemotherapeutic doxorubicin (DOX), which selectively exacerbates RS in cancer cells by promoting replication fork (RF) catastrophe. RSNA converts the excessive reactive oxygen species (ROS) in cancer cells into oxygen, enhancing the DNA-damaging effects of radiotherapy to create more template lesions that impede RF progression in coalition with DOX. After radiation, ROS scavenging by RSNA accelerates RF progression through damaged template strands, increasing the frequency of RF collapse into double-strand breaks. Moreover, pretreatment with RSNA accumulates cancer cells in the S phase, exposing more RFs to radiation-induced RS. These effects of RSNA convergently maximize RS in cancer cells, effectively overcoming the radioresistance of cancer cells without affecting normal cells. Our study demonstrates the feasibility of selectively amplifying RS to boost radiotherapy.

Gefitinib enhances the anti­tumor immune response against EGFR­mutated NSCLC by upregulating B7H5 expression and activating T cells via CD28H.

Gefitinib is a sensitive and effective drug to treat non­small­cell lung cancer (NSCLC) carrying the somatic activating mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR). In the present study, a new mechanism of action of gefitinib in EGFR­mutated NSCLC cells was discovered using in vitro co­culture of NSCLC cells with peripheral blood mononuclear cells (PBMCs). Gefitinib significantly enhanced the cytotoxicity of PBMCs against NSCLC cells expressing mutated EGFR but not in cells expressing wild­type EGFR. Furthermore, it was observed that B7H5 expression was significantly lower in EGFR­mutant cells than in wild­type cells, while inhibition of EGFR by gefitinib or reduction in EGFR using a small interfering RNA (siRNA) both increased the expression of B7H5 in EGFR­mutated NSCLC cells. In addition, when B7H5 expression was reduced by siRNA, the toxic effect of gefitinib was reduced in the co­culture of PBMCs and EGFR­mutant NSCLC cells. In addition, the siRNA­mediated decrease in expression of the B7H5 receptor CD28H in PBMCs also reduced the toxicity of gefitinib on EGFR­mutated NSCLC. Based on these results, it may be proposed that the B7H5/CD28H axis is involved in NSCLC­mediated immunosuppression when EGFR is overactivated. Gefitinib actively inhibits mutated EGFR, which induces B7H5 expression on the cell surface of NSCLC cells, thereby activating CD28H signaling in immune cells, followed by enhanced cytotoxicity against NSCLC. The present study not only provided new insight into the immune evasion mechanism mediated by EGFR mutations but also identified new targets for immune therapy.

Tunable mode-locked fiber laser based on nonlinear multimode interference with double offset-splicing step-index few-mode fiber.

A tunable mode-locked all-fiber Yb-doped laser with a double offset-splicing step-index few-mode fiber (DOS-SIFMF) is demonstrated, to the best of our knowledge, for the first time. The structure of DOS-SIFMF, which constructs a micro Mach-Zehnder interferometer as a consequence of introducing offset splicing, has characteristics of both a saturable absorber and filter and is more accessible to obtain mode-locking operation in an all-normal dispersive region. The results of simulation show that interference with fewer modes is more reliable to acquire mode-locking operation of the fiber laser. The central wavelength, spectrum, and pulse widths are 1032 nm, 6.15 nm, and 28.8 ps, respectively. The output pulse in time and spectrum domains can be tuned in the range of 168.7 ps and 10.7 nm, respectively. This structure has effects of both mode-locking and filtering, showing potential application in communication and sensing. Furthermore, the influence on mode number to interference is generally discussed in the end.

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors.

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+ , promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors.

All-fiber high-power spatiotemporal mode-locked laser based on multimode interference filtering.

Multimode interference (MMI) has been considered to be critical and investigated extensively in mode-locked laser based on single transverse mode systems, whereas there are few researches related to three-dimensional nonlinear dynamics within lasers. In this paper, we demonstrate all-fiber high-power spatiotemporal mode-locked (STML) laser by optimizing MMI filtering, where we find that the MMI filtering plays an important role in counteracting the coupling of high-order modes and improving output power of STML laser. The results under weak coupling condition when the length of graded-index multimode fiber (GIMF) is integral multiple of beat length show that the oscillator generates dissipative soliton pulses at 1036.86 nm with pulse width of 5.65 ps, and the slope efficiency of pump-signal is up to 10.3% with average power/energy of 215 mW/6 nJ, which is the highest among all-fiber STML lasers in normal dispersion regime. Besides, the multiple-soliton of STML, including multiple pulses and harmonic mode-locking can be observed in the experiment. Our work significantly broadens the dimensions of design for all-fiber high-power STML and makes them much more accessible for being put into applications.

LncRNA LIMT (LINC01089) contributes to sorafenib chemoresistance via regulation of miR-665 and epithelial to mesenchymal transition in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide and HCC patients often develop drug resisitene. Long non-coding RNAs (LncRNAs) are closely related to cell cycle, growth, development, differentiation, and apoptosis. Abnormally expressed lncRNAs have been proved to mediate drug resistance in tumor cells. However, the effect of LIMT on drug resistance has not been explored in HCC. In this study, we explored the effect of long non-coding RNA LIMT on drug resistance and its underlying mechanism in hepatocellular carcinoma (HCC). Our results showed that LncRNA LINC01089 (LIMT) expression is downregulated in 78.57% (44/56) of 56 HCC tumor tissue samples. LIMT expression is also downregulated in HCC cells compared with that in normal liver LO2 cells. Inhibition of LIMT increases the resistance to sorafenib and promotes cell invasion via regulation of epithelial to mesenchymal transition (EMT) in HCC. StarBase V3.0 was used to predict the potential binding site of miR-665 in . Furthermore, miR-665 participates in sorafenib resistance and also regulates the level of EMT-related proteins in HCC cells. A rescue experiment demonstrated that silencing of eliminats the inhibitory effect of the miR-665 inhibitor on sorafenib resistance in HCC cells. Taken together, our findings revealed that downregulation of LIMT increases the resistance of HCC to sorafenib via miR-665 and EMT. Therefore, LIMT, which serves as a therapeutically effective target, will provide new hope for the treatment of HCC.

All-fiber dual-wavelength mode-locked fiber laser based on microfiber-assisted NL-MMI.

We present what we believe is a novel approach to generate a dual wavelength in a single fiber-ring oscillator, which is based on microfiber-assisted nonlinear multimode interference. In the software simulation, the mode locker could not only strengthen the spatial filtering and spectral filtering but could also improve the signal-to-noise ratio of the mode-locked pulse over the single mode fiber-graded index multimode fiber-single mode fibers (SMSs). In the experiment, the stable and compact dual-wavelength mode-locked output was achieved by using the proposed mode-locked fiber laser, without any complex controlling electronics. This new optimized mode-locking method provides a compact and low-cost solution for dual-comb systems.

Study of the Cycloaddition of CO2 with Styrene Oxide Over Six-Connected spn Topology MOFs (Zr, Hf) at Room Temperature.

A series of MOFs with a 6-connected spn topology were synthesized (MOF-808-(Zr, Hf), PCN-777-(Zr, Hf), MOF-818-(Zr, Hf)). Through the in situ DRIFTS of NH3 adsorption-desorption, we found that the activated catalyst mainly contains Lewis acid sites. The effects of different organic ligands on the Lewis acid of the Zr6 cluster were analyzed by XPS and NH3 -TPD, and the relative Lewis acidity of the same metal was obtained: PCN-777>MOF-808>MOF-818. In the Py-FTIR results, we confirmed that MOF-818 has a higher acid site density. In the activity test, MOFs with mesoporous structure showed better catalytic activity under normal temperature and pressure. Among them, MOF-818 can still maintain a high degree of crystallinity after catalysis. Finally, we use density functional theory to propose the mechanism of the cycloaddition reaction of carbon dioxide and styrene oxide. The results show that the metal is coordinated with styrene oxide and halogens attack the ß carbon of the epoxide.

WZ4003 sensitizes non-small cell lung cancer cells to gefitinib via inhibition of ARK5 and epithelial-to-mesenchymal transition.

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC); however, its utility is hampered by the development of chemoresistance. This study aimed to investigate the synergistic role of WZ4003, a novel (nua) kinase (NUAK) inhibitor, in enhancing gefitinib sensitivity in NSCLC cells. Our data indicated WZ4003 enhances the sensitivity of NSCLC cells to gefitinib. We also found ARK5 knockdown in NSCLC cell lines increased their sensitivity to gefitinib. However, WZ4003 did not affect gefitinib sensitivity when ARK5 was knocked down in NSCLC cell lines (using siRNA). Both WZ4003 and ARK5 inhibition suppressed epithelial-to-mesenchymal transition by reducing the expression of vimentin and increasing E-cadherin expression. Together, our results demonstrate WZ4003 plays a vital role in releasing acquired resistance to gefitinib by inhibiting ARK5 and epithelial-to-mesenchymal transition. Therefore, synergistic use of WZ4003 and gefitinib may prevent the development of gefitinib resistance in NSCLC.

Inhibition of LncRNA MALAT1 Attenuates Cerebral Ischemic Reperfusion Injury via Regulating AQP4 Expression.

Stroke is one of the leading causes of mortality and disability worldwide. Long noncoding RNAs (lncRNAs) including MALAT1 have been shown to have critical roles in cerebral ischemia reperfusion injury (CIRI). However, the underlying mechanism of MALAT1 in CIRI has not been elucidated. The present study aimed to investigate the function and potential regulatory mechanism of MALAT1 in cerebral ischemic reperfusion injury. We established the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reoxygenation (OGD/RX) model in vivo and in vitro, and then Cell Counting Kit-8 (CCK-8), RT-qPCR, flow cytometry analysis, lactate dehydrogenase (LDH) analysis, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to examine cell viability, MALAT1, aquaporin-4 (AQP4) expression, LDH release, and infarct volume, respectively. The level of AQP4 was remarkably upregulated in CIRI 24 h/48 h or OGD/RX 24 h/48 h compared with the sham group. Knockdown of AQP4 could alleviate OGD/RX-induced injury through enhancing cell viability and reducing LDH release and the rate of apoptotic cells. Furthermore, we found that MALAT1 was also increased in OGD/RX 24 h/48 h and silencing of MALAT1 could decrease AQP4. Inhibition of MALAT1 could also protect OGD/RX-induced injury, while the protective effect of MALAT1 siRNA on cerebral ischemic reperfusion was disappeared after transfection with AQP4 plasmid, indicating that MALAT1 may play a protective role in brain stroke through regulating AQP4. Taken together, our study provides evidence that MALAT1 is involved in ischemic stroke by inhibiting AQP4. Therefore, MALAT1 may serve as a potential target for therapeutic intervention in ischemic brain injury.

Knockdown of eukaryotic translation initiation factor 5A2 enhances the therapeutic efficiency of doxorubicin in hepatocellular carcinoma cells by triggering lethal autophagy.

Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2­mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription­quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient­derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5­ethynyl­2'­deoxyuridine, lactate dehydrogenase release assay and calcein­AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1­dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.

MOF-74-M (M = Mn, Co, Ni, Zn, MnCo, MnNi, and MnZn) for Low-Temperature NH3-SCR and In Situ DRIFTS Study Reaction Mechanism.

Monometallic and bimetallic MOF-74-M (M = Mn, Co, Ni, Zn, MnCo, MnNi, and MnZn) catalysts were prepared by the solvothermal method for NH3-SCR. XRD, BET, SEM, and EDS-mapping tests indicate the successful synthesis of the MOF-74-M catalyst with uniform distribution of metal elements and large specific surface area, and the morphology is almost hexagonal. Adding Mn element to a single-metal catalyst can enhance activity, which is mainly because of the existence of various valence states of Mn so that it has excellent redox properties; the catalytic activity of water and sulfur resistance tests showed that the catalytic activity of MOF-74-M increases after adding a proper amount of SO2, mainly because of the increase in acidic sites. In situ DRIFTS results indicate that the low-temperature range of MOF-74-MnCo and MOF-74-Mn is dominated by the E-R mechanism and the high-temperature range is dominated by the L-H mechanism. The entire temperature range of MOF-74-Zn is dominated by the L-H mechanism.

TBOPP enhances the anticancer effect of cisplatin by inhibiting DOCK1 in renal cell carcinoma.

The treatment of renal cell carcinoma (RCC) with chemotherapy remains a challenge; therefore, improving the knowledge of the molecular mechanisms underlying RCC chemoresistance and developing novel therapeutic strategies is important. Dedicator of cytokinesis 1 (DOCK1), the first member of the DOCK family to be discovered, displays various roles during tumorigenesis; however, its role during RCC progression is not completely understood. Therefore, the present study aimed to clarify the function of DOCK1 and 1­[2­(3'­(trifluoromethyl)­(1,1'­biphenyl)­4­yl)­2­oxoethyl]­5­pyrrolidinylsulfonyl­2 (1H)­pyridone (TBOPP), a DOCK1­sensitive inhibitor, during RCC development and chemoresistance. The results of CCK­8 and EdU assay indicated that TBOPP decreased RCC cell viability and proliferation compared with the control group, and sensitized RCC cells to cisplatin. Moreover, RCC cells with high DOCK1 expression levels displayed increased resistance to cisplatin, whereas DOCK1 knockdown enhanced the lethal effects of cisplatin on RCC cells. Furthermore, the results determined by western blotting, CCK­8 and cell apoptosis assay indicated that TBOPP effectively reduced DOCK1 expression levels compared with the control group, and the TBOPP­mediated cisplatin sensitizing effect was mediated by DOCK1 inhibition. The present study suggests that DOCK1 plays a vital role in RCC cell chemoresistance to cisplatin; therefore, TBOPP may serve as a novel therapeutic agent for RCC chemoresistance.

MiR-223 regulates autophagy associated with cisplatin resistance by targeting FBXW7 in human non-small cell lung cancer.

BACKGROUND: Cisplatin is widely used as a first-line treatment for non-small cell lung cancer (NSCLC), but chemoresistance remains a major clinical obstacle for efficient use. As a microRNA, miR-223 was reported to promote the doxorubicin resistance of NSCLC. However, whether miR-223 is also involved in cisplatin resistance of NSCLC and the mechanism miR-223 involved in drug resistance is unclear. Accumulated evidence has shown that abnormal autophagy is associated with tumor chemoresistance. The study aimed to study the role of miR-223 on cisplatin sensitivity in NSCLC and uncover the potential mechanisms. METHODS: NSCLC cells transfected with mimic or inhibitor for miR-223 was assayed for chemoresistance in vitro. MiR-223 expression was assessed by quantitative real-time PCR (qRT-PCR). Western blot were used to study the expression level of F-box/WD repeat-containing protein 7 (FBXW7) and autophagy-related protein. The effect of miR-223 on cisplatin sensitivity was examined by using CCK-8, EdU assays and Autophagic flux assay. Luciferase assays, EdU assays and small interfering RNA were performed to identify the targets of miR-223 and the mechanism by which it promotes treatment resistance. Xenograft models were established to investigate the effect of mir-223 on cisplatin sensitivity. RESULTS: In the present study, we found that the level of miR-223 was significantly positively correlated with cisplatin resistance. MiR-223 overexpression made NSCLC cells resistant to cisplatin treatment. We further found that autophagy mediated miR-223-mediated cisplatin resistance in NSCLC cells. Further mechanistic research demonstrated that miR-223 directly targeted FBXW7. The overexpression of miR-223 could inhibit the level of FBXW7 protein expression, thus promoting autophagy and making NSCLC cells resistant to cisplatin. Finally, we confirmed the increased effect of cisplatin sensitivity by miR-223 Antagomir in xenograft models of NSCLC. CONCLUSIONS: Our results demonstrate that miR-223 could enhance autophagy by targeting FBXW7 in NSCLC cells. Inhibition of autophagy by miR-223 knockdown provides a novel treatment strategy to alleviate cisplatin resistance in NSCLC.

Chimeric peptide supramolecular nanoparticles for plectin-1 targeted miRNA-9 delivery in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis. Insights into the roles of MicroRNAs (miRNAs) in diseases, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Methods: Here, we employed a novel chimeric peptide supramolecular nanoparticle delivery system for plectin-1 (PL-1)-targeted PDAC-specific miR-9 delivery in vitro and in pancreatic cancer patient-derived xenograft (PDX) model. RT-PCR and immunohistochemistry (IHC) were conducted to detect the expression pattern of eIF5A2. mRFP-GFP-LC3 fluorescence microscopy and Western blot were carried out to determine autophagy. Luciferase reporter assays were performed to elucidate the regulatory role of miR-9/eIF5A2 axis. Results: PL-1/miR-9 nanocomplexes dramatically improve the anticancer effect of doxorubicin through downregulating eIF5A2 expression to inhibit autophagy and induce apoptosis in PDAC therapy in vivo. Mechanistically, miR-9 directly targets the eIF5A2 transcript by binding to its 3'-untranslated region (3'-UTR) to reduce the expression levels and the secreted protein of eIF5A2 in PDAC cells. Conclusion: PL-1/miR-9 nanoparticles can be used as a novel promising anti-cancer strategy with tumor targeting and miR-9/eIF5A2 may serve as a new potential therapeutic target for future synergic therapy against human PDAC.

Reduction of Bladder Cancer Chemosensitivity Induced by the Effect of HOXA-AS3 as a ceRNA for miR-455-5p That Upregulates Notch1.

Chemoresistance is one of the main causes of recurrence in bladder cancer patients and leads to poor prognosis. Recently, long non-coding RNAs, like HOXA-AS3, have been reported to regulate chemoresistance in several types of cancer. In this study, we aimed to determine whether HOXA-AS3 can mediate cisplatin resistance in bladder cancer, and its potential mechanism of action. We determined the viability, proliferation, and apoptosis of bladder cancer cells using a CCK-8 assay, EdU staining, and flow cytometry, respectively. We used western blot analysis to assess the expression of markers of epithelial-mesenchymal transition (EMT) and Notch1. We then confirmed expression of these EMT-related markers by immunofluorescence analysis. We found that hypoxia promoted resistance to cisplatin and upregulated the level of HOXA-AS3 in BC cells. Inhibition of HOXA-AS3 enhanced hypoxia-induced cisplatin sensitivity by regulating EMT and Notch1 in BC cells. A dual-luciferase reporter assay confirmed that HOXA-AS3 directly targets miR-455-5p and that Notch1 was a potential target of miRNA-455-5p. We also found that the positive effect of HOXA-AS3 inhibition on cisplatin resistance and tumorigenesis was alleviated when BC cells were transfected with miR-455-5p. Finally, we showed combining HOXA-AS3 small interfering RNA (siRNA) with cisplatin treatment inhibited tumorigenesis in a BALB/c nu/nu mouse model. Our findings indicate that HOXA-AS3 may function as a competing endogenous RNA (ceRNA) of miR-455-5p to regulate Notch1 and play an important role in regulating chemotherapeutic drug sensitivity in BC cells. Therefore, HOXA-AS3 may be a novel therapeutic target for treating bladder cancer.

miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4.

Acquired resistance to chemotherapy is a major obstacle in breast cancer (BC) treatment. Accumulated evidence has uncovered that microRNAs (miRNAs) are vital regulators of chemoresistance in cancer. Growing studies reveal that miR-137 acts as a suppressor in tumor progression. However, it remains obscure the role of miR-137 in modulating the sensitivity of BC cells to doxorubicin (DOX). In this study, we demonstrate that miR-137 exerts a significant effect on repressing the development of chemoresistance of BC cells in response to DOX via attenuating epithelial-mesenchymal transition (EMT) of tumor cells in vitro and in vivo. MiR-137 overexpression dramatically elevated the sensitivity of BC cells to DOX as well as impaired the DOX-promoted EMT of tumor cells. Mechanistically, miR-137 directly targeted dual-specificity phosphatase 4 (DUSP4) to impact on the EMT and chemoresistance of BC cells upon DOX treatment. Consistently, decreased DUSP4 efficiently enhanced the sensitivity of BC cells to DOX while overexpressed DUSP4 significantly diminished the beneficial effect of miR-137 on BC cells chemoresistance. Moreover, the increased miR-137 heightened the sensitivity of BC cells-derived tumors to DOX through targeting DUSP4 in vivo. Together, our results provide a novel insight into the DOX resistance of BC cells and miR-137 may serve as a new promising therapeutic target for overcoming chemoresistance in BC.