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1.
Mol Ther Nucleic Acids ; 27: 718-732, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35317282

RESUMO

Drug discovery from plants usually focuses on small molecules rather than such biological macromolecules as RNAs. Although plant transfer RNA (tRNA)-derived fragment (tRF) has been associated with the developmental and defense mechanisms in plants, its regulatory role in mammals remains unclear. By employing a novel reverse small interfering RNA (siRNA) screening strategy, we show that a tRF mimic (antisense derived from the 5' end of tRNAHis(GUG) of Chinese yew) exhibits comparable anti-cancer activity with that of taxol on ovarian cancer A2780 cells, with a 16-fold lower dosage than that of taxol. A dual-luciferase reporter assay revealed that tRF-T11 directly targets the 3' UTR of oncogene TRPA1 mRNA. Furthermore, an Argonaute-RNA immunoprecipitation (AGO-RIP) assay demonstrated that tRF-T11 can interact with AGO2 to suppress TRPA1 via an RNAi pathway. This study uncovers a new role of plant-derived tRFs in regulating endogenous genes. This holds great promise for exploiting novel RNA drugs derived from nature and sheds light on the discovery of unknown molecular targets of therapeutics.

2.
Acta Pharm Sin B ; 12(2): 821-837, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35251919

RESUMO

Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-ß2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-ß2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-ß2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-ß2; the expressions of both miR-7-5p and TGF-ß2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-ß2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

3.
Bioact Mater ; 13: 23-36, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35224289

RESUMO

Curcumenol, an effective ingredient of Wenyujin, has been reported that exerted its antitumor potential in a few cancer types. However, the effect and molecular mechanism of curcumenol in lung cancer are largely unknown. Here, we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells. Next, we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time. Subsequently, using RNA sequencing, we found that the long non-coding RNA H19 (lncRNA H19) was significantly downregulated in lung cancer cells treated with curcumenol, when compared to untreated controls. Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol, while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis. In conclusion, our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Therefore, our findings will hopefully provide a valuable drug for treating lung cancer patients.

4.
Cancer Lett ; 515: 36-48, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34052328

RESUMO

Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.


Assuntos
Apigenina/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Luteolina/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interferon gama/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus
6.
Integr Cancer Ther ; 18: 1534735419890020, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31838881

RESUMO

Conventional methods in treating non-small cell lung cancer contain surgery, chemotherapy, radiotherapy, and targeted therapy, which have various defects. Recently, with the deeper research on tumor immunity, immunotherapy has made the breakthrough in the treatment of cancers. Especially developments of programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the therapy into a new stage. This review mainly focuses on introducing existing monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1 expression, tumor mutation burden, and microsatellite instability. By understanding the resistance mechanism of anti-PD-1/L1 blockade, research is further improving the survival benefit and expanding the benefit population. So, PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies clinically. Discussion and comparison of their effectiveness and safety are also comprehensively reviewed. Meanwhile, we explore the potential, the impact, and mechanisms of combining traditional Chinese medicine with immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/metabolismo , Humanos , Imunoterapia/métodos , Medicina Tradicional Chinesa/métodos
7.
Pharmacol Res ; 144: 158-166, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991106

RESUMO

Chronic atrophic gastritis (CAG) is a common digestive disease without specific treatment. According to syndrome differentiation, traditional Chinese medicine (TCM) classified it into different syndromes and has achieved significant therapeutic effects. In this study, immune repertoire sequencing techniques combined with symptom scores, electronic gastroscopy as well as pathologic changes were used to evaluate the effect and the underlying mechanism of Modified Sijunzi Decoction (MSD) in treating CAG. The results showed that MSD could relieve CAG symptoms, improve pathologic changes in CAG with fatigue and tiredness symptom, but with no help in CAG with reversal heat symptom. Moreover, MSD could regulate immune disorders in CAG with fatigue and tiredness symptom, and 7 TCR biomarkers were explored in CAG patients with immune disorders. All these results indicated that MSD is effective in treating CAG patients with fatigue and tiredness symptom by tonifying the spleen qi, suggesting that CAG treatment based on syndrome differentiation is reasonable.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Gastrite Atrófica/tratamento farmacológico , Gastrite Atrófica/patologia , Adulto , Idoso , Doença Crônica , Feminino , Humanos , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Estômago/efeitos dos fármacos , Estômago/patologia
8.
Oncogene ; 37(10): 1354-1368, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269867

RESUMO

Abnormalities in epigenetic modifiers are emerging as driving events in prostate cancer (PCa). The histone methyltransferase KMT2D, a frequently aberrant epigenetic modifier in various tumors, has an undefined role in PCa. Moreover, little is known regarding KMT2D's mutation in Chinese patients or its downstream signaling pathways and targets. Here, we profiled the mutational spectrum of 32 significantly PCa-associated genes by using disease-targeted sequencing, and found that KMT2D was highly mutated (63.04%, 29/46) in Chinese patients. Moreover, high KMT2D transcription was also associated with poor prognosis in an independent cohort (n = 51). In KMT2D-knockdown PC-3 and DU145 cells, cell proliferation (P < 0.01), invasion (P < 0.001), and migration (P < 0.01) were consequently suppressed. KMT2D depletion effectively suppressed tumor growth by 92.21% in vivo. Notably, integrative analyses of RNAseq and ChIPseq characterized two crucial genes downregulated by KMT2D, leukemia inhibitory factor receptor (LIFR) and Kruppel-like factor-4 (KLF4), which are regulators in PI3K/Akt and EMT, respectively. Our present study revealed that KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting LIFR and KLF4 and thus serves as a putative epigenetic-based target for treating PCa.


Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição Kruppel-Like/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Proteínas de Ligação a DNA/genética , Epigênese Genética/fisiologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Células PC-3 , Próstata/patologia , Transdução de Sinais/genética , Ativação Transcricional/genética , Células Tumorais Cultivadas
9.
Oncotarget ; 8(67): 111119-111129, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29340042

RESUMO

Rheumatoid arthritis (RA) is a highly prevalent chronic autoimmune disease. However, genetic and environmental factors involved in RA pathogenesis are still remained largely unknown. To identify the genetic causal variants underlying pathogenesis and disease progression of RA patients, we undertook the first comprehensive whole-exome sequencing (WES) study in a total of 124 subjects including 58 RA cases and 66 healthy controls in Han Chinese population. We identified 378 novel genes that were enriched with deleterious variants in RA patients using a gene burden test. The further functional effects of associated genetic genes were classified and assessed, including 21 newly identified genes that were involved in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, focal adhesion and glycerophospholipid metabolism pathways relevant to RA pathogenesis. Moreover, six pathogenic variants were investigated and structural analysis predicted their potentially functional alteration by homology modeling. Importantly, five novel and rare homozygous variants (NCR3LG1, RAP1GAP, CHCHD5, HIPK2 and DIAPH2) were identified, which may exhibit more functional impact on RA pathogenesis. Notably, 7 genes involved in the olfactory transduction pathway were enriched and associated with RA disease progression. Therefore, we performed an efficient and powerful technique WES in Chinese RA patients and identified novel, rare and common disease causing genes that alter innate immunity pathways and contribute to the risk of RA. Findings in this study may provide potential diagnostic tools and therapeutic strategies for RA patients.

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