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

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.

scholarly journals MXD1 is a Potential Prognostic Biomarker and Correlated With Specific Molecular Change and Tumor Microenvironment Feature in Esophageal Squamous Cell Carcinoma

2021 ◽  
Vol 20 ◽  
pp. 153303382110521
Author(s):  
Feng Du ◽  
Dezuo Dong ◽  
Xiaodong Zhang ◽  
Jun Jia
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Messenger Rna ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Characteristics ◽  
Related Gene ◽  
Mesenchymal Transition ◽  
Gene Sets

Background: Identification of novel biomarkers is crucial for the diagnosis and treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to reveal the clinical significance and molecular characteristics of MYC-associated factor X dimerization protein 1 (MXD1) in ESCC. Patients and methods: We collected 3 ESCC cohorts to investigate the effect of MXD1 on clinical outcomes. In addition, we compared and analyzed the possible transcription changes between MXD1-low and MXD1-high ESCC patients using bioinformatics. Moreover, immunohistochemical analysis was conducted to confirm the potential impact of MXD1 on the prognosis and tumor immune microenvironment (TIME). Results: MXD1 messenger RNA (mRNA) expression was significantly lower in tumors than in normal tissues. Low expression of MXD1 in ESCC was associated with a more aggressive tumor stage and worse prognosis at both the mRNA and protein levels. Moreover, MXD1-low ESCC showed upregulation of epithelial–mesenchymal transition and extracellular matrix-related gene sets, and significantly higher NFE2L2 and KIAA1324L mutation frequencies. In contrast, MXD1-high ESCC showed upregulation of tumor differentiation and immune-related gene sets. Furthermore, the CIBERSORT approach showed that high expression of MXD1 was associated with a higher proportion of neutrophils but a lower proportion of M2 macrophages. At the protein level, MXD1 expression was positively correlated with programmed cell death 1 ligand 1 (PDL1) and CD8 expression. In silico analysis predicted that MXD1-high ESCC was more likely to benefit from immunotherapy. Conclusion: This study suggests that MXD1 is a crucial prognostic factor in ESCC patients and is closely associated with specific transcriptional changes and TIME features.

scholarly journals SIX1 Down-Regulation Influence Drug Resistance, Epithelial-Mesenchymal Transcription Factors and Self-Renewal Capacity in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Pelin Balcik Ercin ◽  
Arzu Aysan ◽  
Nazli Salik ◽  
Esma Erciyas
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Expression Profile ◽  
Epithelial Mesenchymal Transition ◽  
Profile Analysis ◽  
Sorafenib Treatment ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Sine Oculis

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.

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

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2883 ◽  
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.

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

2020 ◽  
Vol 29 ◽  
pp. 096368972092998 ◽  
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.

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

2019 ◽  
Vol 20 (15) ◽  
pp. 3736 ◽  
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.

scholarly journals Pathogenesis and characteristics of large ameloblastoma of the jaw: a report of two rare cases

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110148
Author(s):  
Xue Qiao ◽  
Xing Niu ◽  
Jiayi Liu ◽  
Lijie Chen ◽  
Yan Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Molecular Evidence ◽  
Nucleotide Polymorphisms ◽  
Related Gene ◽  
Epithelial Tumor ◽  
Single Nucleotide ◽  
Mesenchymal Transition ◽  
Hras Gene

Ameloblastoma is a common odontogenic epithelial tumor that exhibits various biological behaviors, ranging from simple cystic expansion to aggressive solid masses characterized by local invasiveness, a high risk of recurrence, and even malignant transformation. We report on two cases of unusually large solid ameloblastomas. We detected epithelial–mesenchymal transition-related gene expression and HRAS gene single nucleotide polymorphisms, providing possible molecular evidence of mesenchymal morphological changes in ameloblastoma. The detailed analysis of the pathogenesis of these two cases of ameloblastoma may deepen our understanding of this rare disease and offer promising targets for future targeted therapy.

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

Molecules ◽  
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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