Six2 is negatively correlated with good prognosis and decreases 5-FU sensitivity via suppressing E-cadherin expression in hepatocellular carcinoma cells

Li, Jian-Wang; Huang, Can; Li, Jianhua; Yuan, Jianhua; Chen, Qionghui; Zhang, Weifang; Xu, Zhen-Sheng; Liu, Yingping; Li, Yong; Zhan, Meixiao; Lu, Ligong

doi:10.1016/j.biopha.2018.05.032

Cited by 8 publications

(10 citation statements)

References 14 publications

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“…Previous studies have shown that six2 is required for DDX3‐mediated tumour aggressiveness and cetuximab resistance in KRAS‐wild‐type colorectal cancer, has been confirmed to facilitate breast cancer metastasis . Recent study has demonstrated that six2 is negatively correlated with good prognosis and decreases 5‐FU sensitivity in hepatocellular carcinoma cells via regulating cell stemness . However, the roles and related mechanism in NSCLC progression are still unclear.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Six2 promotes non–small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E‐cadherin

Hou

Cong

et al. 2019

Cell Proliferation

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Objectives The roles and related mechanisms of six2 in regulating non–small cell lung cancer (NSCLC) cells progression are unclear. This work aimed to explore the roles of six2 in NSCLC cell stemness. Materials and Methods Kaplan‐Meier plotter analysis was used to examine the correlation between six2 expression and the survival of NSCLC patients. Quantitative reverse transcription PCR and Western blot were performed to detect six2 expression in clinical samples. Moreover, transwell migration, tumour spheroid formation and in vivo tumour formation assays were used to examine the effects of six2 on NSCLC cell progression. Additionally, methylation analysis was carried out to measure E‐cadherin methylation level in different cells. Finally, cell viability assay was performed to explore the effects of six2 on chemotherapeutic sensitivity of NSCLC cells. Results Lung cancer patients with a higher six2 expression level displayed a shorter overall survival. Six2 expression was higher in lung cancer tissues than in normal adjacent tissues. Additionally, six2 knockdown suppressed NSCLC cell stemness. Mechanistically, six2 overexpression inhibited epithelial marker E‐cadherin expression via stimulating its promoter methylation. And E‐cadherin knockdown rescued six2 knockdown‐induced decrease of NSCLC cancer cell stemness. Notably, six2 knockdown enhanced cisplatin sensitivity in parental NSCLC cells and attenuated cisplatin resistance in cisplatin‐resistant NSCLC cells. Conclusions Our results suggest that six2 facilitates NSCLC cell stemness and attenuates chemotherapeutic sensitivity via suppressing E‐cadherin expression.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Six2 promotes non–small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E‐cadherin

Hou

Cong

et al. 2019

Cell Proliferation

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“…Previous studies have shown that the intraocular homologous box (SIX) transcription factor SIX2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression; 57 the SIX2 level is correlated with poor prognosis, and elevated SIX2 has been shown to decrease the sensitivity of hepatocellular carcinoma cells to 5-FU. 58 Wu et al (2017) found that DDX3 -mediated cetuximab resistance can be regulated by the YAP1/SIX2 axis in KRAS -WT CRCs, 59 and further confirmed that SIX2 had prognostic value (albeit only in KRAS -WT CRC patients). 57 – 59 These findings from previous studies support the utility of the predictive biomarkers we identified with the HNSCC PCTs.…”

Section: Discussionmentioning

confidence: 93%

Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

Yao

Wang

Chen

et al. 2022

Sig Transduct Target Ther

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Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, and its response duration is limited by drug resistance. Here, we conducted randomized “Phase II-like clinical trials” of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab (e.g., amplification of ANKH, up-regulation of PARP3). After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort (61 PDX models), we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms. Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs, including the emergence of subclones with strongly activated RAS/MAPK. Extending these insights, we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo. Beyond revealing intrinsic resistance biomarkers, our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.

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“…Silenced Six2 in adult kidneys was found reactivated in renal carcinoma and its misexpression has been linked to the etiology of renal cancer [12,18]. Six2 also plays an important part in cell growth and metastasis in hepatocellular carcinoma and regulates cell stemness by affecting epithelial-to-mesenchymal transition (EMT) and facilitating drug resistance in lung cancer [14,29]. In breast cancer, it is demonstrated that Six2 promotes distant metastasis through downregulating E-cadherin levels and upregulating Sox2 expression by directly binding with the srr2 enhancer of Sox2 [13,17].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of Six2-mediated transcriptional regulatory network in ccRCC

Tian

Yang

et al. 2022

Preprint

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BackgroundSix2, a transcription factor, exerts an oncogenic role in clear cell renal cell carcinoma (ccRCC). Increased Six2 expression could enhance cancer metastasis. However, the regulatory action of Six2 remains unclear in cancer. The purpose of this study is to analyze the regulatory pattern and potential downstream effectors of Six2.MethodsFirstly, transcriptional data in TCGA-KIRC cohorts was used to analyze the relationship between Six2 expression and clinical information. Then, we analyzed Six2-related differentially expressed genes (DEGs) and constructed a prognostic model using the Lasso-Cox algorithm by integrating Six2 ChIP data and co-expressed genes. Next, we analyzed the clinical significance of this model and examined the DEGs between the high-and low-risk group. Finally, we intersected the GO and KEGG pathway results between Six2-related DEGs and risk-related DEGs to reveal biological functions in which Six2 is involved.ResultsSix2 was increased in RCC cells compared with normal kidney cells and upregulated Six2 was positively linked with clinical stage, M stage, and worse survival. Potential downstream effectors and biological functions regulated by Six2 were identified using in silico analysis. Meanwhile, a risk model based on 8 Six2 target genes was established to classify ccRCC patients into high-and-low groups. This risk model showed a reliable ability to forecast the overall survival of ccRCC patients. Shared enriched pathways were found between the Six2 high-and low-expression and risk groups, such as epithelial-to-mesenchymal transition, PI3K-Akt pathway, etc.ConclusionOur findings provide a promising prognostic indicator for ccRCC patients and help better understand the transcriptional role of Six2 in ccRCC.

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Six2 is negatively correlated with good prognosis and decreases 5-FU sensitivity via suppressing E-cadherin expression in hepatocellular carcinoma cells

Cited by 8 publications

References 14 publications

RETRACTED: Six2 promotes non–small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E‐cadherin

RETRACTED: Six2 promotes non–small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E‐cadherin

Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

Comprehensive analysis of Six2-mediated transcriptional regulatory network in ccRCC

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