MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer

Abstract Sine oculis homeoprotein 1 (SIX1) was discovered to exert an essential role in embryonic development and it was also identified to be re-activated in various types of mammalian cancer. Immunohistochemical and SIX1 gene expression analyses were performed to determine the prognostic role of SIX1 expression. SIX1 expression was suppressed by short hairpin RNA transduction in the SNU398 HCC cell line. The effects of SIX1 on proliferation, epithelial-mesenchymal transition, apoptosis, drug resistance, and sphere formation were assessed in SIX1 knock-down cells. The upregulated expression levels of SIX1 were revealed to be correlated with the stage of the disease in breast, colon and liver cancer, with liver cancer exhibiting the highest expression profile. SIX1 knockdown significantly affected the cell morphology, proliferation, downregulated the protein expression levels of ZEB1, ZEB2 and SNAI1 and upregulated the expression levels of TWIST1 in hepatocellular carcinoma cells. Furthermore, SIX1 knockdown cells were more sensitive to sorafenib treatment; however, the expression profile analysis of the drug resistance genes ABCB1, ABCC1 and ABCG2 did not explain this sensitivity. Finally, SIX1 knockdown cells were identified to have decreased CD90 levels and lost their sphere-forming ability, which is essential for cancer stem cell properties. Overall, these results indicated that SIX1 expression may be useful as a diagnostic marker for patients with HCC.

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Heterogeneity, Inherent and Acquired Drug Resistance in Patient-Derived Organoids Models of Primary Liver Cancer

10.21203/rs.3.rs-1229184/v1 ◽

2022 ◽

Author(s):

Guang-Wen Cao ◽

Linfeng Xian ◽

Pei Zhao ◽

Xi Chen ◽

Zhimin Wei ◽

...

Keyword(s):

Drug Resistance ◽

Liver Cancer ◽

Mouse Models ◽

Epithelial Mesenchymal Transition ◽

Primary Liver Cancer ◽

Related Gene ◽

S6 Kinase ◽

Acquired Drug Resistance ◽

Mesenchymal Transition ◽

Gene Sets

Abstract To screen for sensitive drugs for recurrent primary liver cancer (PLC) and elucidate the mechanisms underlying inherent and acquired drug resistance, we established a platform of organoids, organoids-derived xenograft (ODX) mouse models, and patient-derived xenograft (PDX) mouse models of primary liver cancer (PLC). Fifty-two organoids were established from 153 PLC patients. Establishing organoids of hepatocellular carcinoma (HCC) displayed a trend toward a higher success rate than establishing PDX (29.0% vs. 23.7%) and took a shorter duration (13.0 ± 4.7 vs. 25.1 ± 5.4 days, P=2.28×10−13) than establishing PDX models. Larger tumor, vascular invasion, and advanced stage were significantly associated with successful establishment of organoids and PDX in HCC. Organoids and ODX recapitulated PLC histopathological features but enriched more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive in ODX model, indicating innate immunity plays a role. Acquired sorafenib-resistant HCC organoids were generated via 3–5 months of induction. RNA-sequencing indicated that stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated, in acquired sorafenib-resistant organoids. Targeting mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were often associated with unfavorable prognosis. Conclusively, HCC organoids perform better than PDX for drug selection. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating the stemness, retrodifferentiation, and EMT. Phosphorylated S6 kinase might be predictive for drug resistance in HCC.

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Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

Molecules ◽

10.3390/molecules25122883 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2883 ◽

Cited By ~ 1

Author(s):

Keiko Takagi ◽

Yutaka Midorikawa ◽

Tadatoshi Takayama ◽

Hayato Abe ◽

Kyoko Fujiwara ◽

...

Keyword(s):

Liver Cancer ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Tumor Grade ◽

Expression Level ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Liver Cancer Cells ◽

Tgf Β1

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.

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LncRNA DLX6-AS1 Contributes to Epithelial–Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis

Cell Transplantation ◽

10.1177/0963689720929983 ◽

2020 ◽

Vol 29 ◽

pp. 096368972092998 ◽

Cited By ~ 1

Author(s):

Chuang Du ◽

Yan Wang ◽

Yingying Zhang ◽

Jianhua Zhang ◽

Linfeng Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Drug Resistance ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cisplatin Resistance ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Expression Levels

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

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Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20153736 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3736 ◽

Cited By ~ 12

Author(s):

Sabino Russi ◽

Henu Kumar Verma ◽

Simona Laurino ◽

Pellegrino Mazzone ◽

Giovanni Storto ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Epithelial Mesenchymal Transition ◽

Current Approach ◽

Gastric Cancer Cells ◽

Drug Induced ◽

Cytotoxic Effects ◽

Mesenchymal Transition ◽

Damage Response ◽

Drug Detoxification

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.

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Current insights on extracellular vesicle-mediated glioblastoma progression: Implications in drug resistance and epithelial-mesenchymal transition

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2021.130065 ◽

2021 ◽

pp. 130065

Author(s):

Swagatama Mukherjee ◽

Prakash P. Pillai

Keyword(s):

Drug Resistance ◽

Epithelial Mesenchymal Transition ◽

Extracellular Vesicle ◽

Mesenchymal Transition

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Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review

Molecules ◽

10.3390/molecules26195792 ◽

2021 ◽

Vol 26 (19) ◽

pp. 5792

Author(s):

Tiantian Tan ◽

Jie Li ◽

Ruhua Luo ◽

Rongrong Wang ◽

Liyan Yin ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Tumor Resistance ◽

Mesenchymal Transition ◽

Life Threatening ◽

The Common ◽

Abcb1 Transporter

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells’ sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial–mesenchymal transition, and so on. In this paper, the mechanisms of elemene’s reversal of drug resistance are comprehensively reviewed.

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Value of Biomarkers in Liver Cancer EMT model under different interventions：A meta-analysis

10.21203/rs.3.rs-892562/v2 ◽

2021 ◽

Author(s):

Jing Yan ◽

Shuli Zou ◽

Bei Xie ◽

Ye Tian ◽

Zhiheng Peng ◽

...

Keyword(s):

Liver Cancer ◽

Epithelial Mesenchymal Transition ◽

Gene Knockout ◽

Meta Analysis ◽

China National Knowledge Infrastructure ◽

Mesenchymal Transition ◽

Tumor Microenvironments ◽

Genetic Intervention ◽

E Cadherin

Abstract Background There are various interventions to establish the Liver cancer epithelial-mesenchymal transition (EMT) models. However, the ideal biomarkers for unique model are not well established. Further studies are necessary to evaluation of effective EMT biomarkers under different interventions in vitro studies. A meta-analysis was performed to evaluate the performance of different biomarkers in HepG2 cells during EMT under multiple interventions. Methods PubMed, Web of Science, Embase, the China National Knowledge Infrastructure (CNKI), the China Biology Medicine disc (CBM), Wan Fang Data, and VIP databases were systematically searched from inception to June 14, 2020 by two independent reviewers. Results A total of 58 studies were included in the meta-analysis. Our study showed that E-cadherin responds well to the intervention of medication, genetic intervention, gene knockout/knockdown, hypoxia, and other tumor microenvironments, as well as non-coding RNA (ncRNA) overexpression and silencing. N-cadherin can effectively evaluate the intervention effect of medication, genetic intervention, hypoxia and other tumor microenvironments, as well as ncRNA overexpression. Vimentin reflects the effects of medication, pro-EMT genetic intervention and gene knockout/knockdown, anti-EMT ncRNA overexpression and anti-EMT ncRNA silencing and hypoxia. Snail only responds to the intervention of anti-EMT genetic intervention and gene knockout/knockdown, tumor microenvironments other than hypoxia, anti-EMT ncRNA overexpression and ncRNA silencing. Conclusions Our results shows that some medicine, some gene, microenvironment and some ncRNA can effectively induce/inhibit EMT process. E-cadherin, N-cadherin, Vimentin and Snail are effective biomarkers during this process. They respond differently to different intervention. Therefore, different biomarkers should be chosen under different intervention based on their performance.

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