The ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes <i>ERCC1</i> and <i>ERCC4</i> in colorectal cancer

Sreekumar, Rahul; AlSaihati, Hajir; Emaduddin, Muhammad; Moutasim, Karwan A.; Mellone, Massimiliano; Patel, Ashish; Kılıç, Seval; Çetįn, Metin; Erdemir, Sule; Navio, Marta Salgado; Lopez, Maria A.; Curtis, Nathan; Yağcı, Tamer; Primrose, John; Price, Brendan D.; Berx, Geert; Thomas, Gareth J.; Tulchinsky, Eugene; Mirnezami, Alex H.; Sayan, Emre

doi:10.1002/1878-0261.12965

Cited by 20 publications

(12 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EMT is a process during which epithelial cells lose their polarity and acquire a mesenchymal phenotype, which is an important process for promoting tumor invasiveness and metastasis ( 29 ). It is commonly characterized by downregulation of E-cad, which is a key epithelial marker, along with upregulation of N-cad, vimentin and ZEB2, which are crucial mesenchymal marker genes ( 30 , 31 ). As presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

TAGLN2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of colorectal cancer cells by activating STAT3 signaling through ANXA2

Zhao

Lü

2021

Oncol Lett

View full text Add to dashboard Cite

Colorectal cancer (CRC) is one of the leading causes of cancer-associated mortality worldwide and currently ranks third in the USA in terms of prevalence. Transgelin-2 (TAGLN2) was previously reported to serve as a tumor promoter in various types of cancer. The present study aimed to investigate the role of TAGLN2 in the progression of CRC and to determine the potential underlying mechanism. The expression level of TAGLN2 in CRC cells (HCT116, SNU-C1, LoVo and SW480) were first detected by reverse transcription quantitative PCR and western blotting. Following TAGLN2 knockdown through transfection with short hairpin (sh)RNAs against TAGLN2, CRC cell proliferation was determined using Cell Counting Kit-8 and 5'-ethynyl-2'-deoxyuridine assays. Cell migration and invasion were evaluated using wound healing and Transwell assays, respectively. The expression levels of matrix metalloproteinase (MMP)2, MMP9 and proteins associated with epithelial-mesenchymal transition (EMT), including N-cadherin (N-cad), vimentin, zinc finger E-box binding homeobox 2 (ZEB2) and E-cadherin (E-cad), were also evaluated by western blotting. Furthermore, following TAGLN2 overexpression and the use of signal transducer and activator of transcription 3 (STAT3) inhibitors to treat CRC cells, all the aforementioned biological parameters were evaluated. The potential relationship between annexin 2 (ANXA2) and STAT3 was confirmed by western blotting analysis. The expression level of TAGLN2 was found to be particularly high in CRC cells. Following TAGLN2 knockdown, CRC cell proliferation, migration, invasion and EMT were significantly inhibited. TAGLN2 knockdown also suppressed STAT3 phosphorylation in CRC cells. In addition, the promoting effects of TAGLN2 overexpression on the progression of CRC were reversed by STAT3 inhibitor. Furthermore, ANXA2 was positively associated with STAT3. Taken together, these findings demonstrated that TAGLN2 could promote the proliferation, invasion, migration and EMT of CRC cells by activating STAT3 and regulating ANXA2 expression. This may reveal the underlying mechanism by which TAGLN2 might regulate the progression of CRC and provide potential therapeutic targets for the treatment of CRC.

show abstract

Section: Resultsmentioning

confidence: 99%

TAGLN2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of colorectal cancer cells by activating STAT3 signaling through ANXA2

Zhao

Lü

2021

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…ZEB2 increases the nucleotide excision repair (NER) pathway activity. In colorectal cancer, ZEB2 enhances resistance of cancer cells to oxaliplatin‐induced DNA damage, by increasing NER capacity by upregulation of the ERCC1 gene 90 . Again, in this case, ZEB2‐mediated EMT is instrumental in increasing genomic stability and cell survival.…”

Section: Discussionmentioning

confidence: 99%

Role of EMT in the DNA damage response, double‐strand break repair pathway choice and its implications in cancer treatment

Seimiya

2022

Cancer Science

View full text Add to dashboard Cite

Numerous epithelial–mesenchymal transition (EMT) characteristics have now been demonstrated to participate in tumor development. Indeed, EMT is involved in invasion, acquisition of stem cell properties, and therapy‐associated resistance of cancer cells. Together, these mechanisms offer advantages in adapting to changes in the tumor microenvironment. However, recent findings have shown that EMT‐associated transcription factors (EMT‐TFs) may also be involved in DNA repair. A better understanding of the coordination between the DNA repair pathways and the role played by some EMT‐TFs in the DNA damage response (DDR) should pave the way for new treatments targeting tumor‐specific molecular vulnerabilities, which result in selective destruction of cancer cells. Here we review recent advances, providing novel insights into the role of EMT in the DDR and repair pathways, with a particular focus on the influence of EMT on cellular sensitivity to damage, as well as the implications of these relationships for improving the efficacy of cancer treatments.

show abstract

“…Due to the relatively slow advancement of new agents to substitute traditional chemotherapeutics, predicting whether the patient will develop fluoropyrimidine-based chemotherapy resistance is critical in achieving effective clinical management of patients with CRC. Many biomarkers have been shown to be associated with fluoropyrimidine-based chemotherapy resistance, such as complement component 3 ( 31 ), ZEB2 ( 32 ), and PKM2 ( 33 ). These biomarkers may help identify patients who are suitable for fluoropyrimidine-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Guo

Lei

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

BackgroundTumor-infiltrating immune cells (TIICs) are associated with chemotherapy response. This study aimed to explore the prognostic value of a TIIC-related tumor microenvironment score (TMEscore) in patients with colorectal cancer (CRC) who underwent chemotherapy and construct a TMEscore-related gene signature to determine its predictive value.MethodsGene profiles of patients who underwent fluoropyrimidine-based chemotherapy were collected, and their TIIC fractions were calculated and clustered. Differentially expressed genes (DEGs) between clusters were used to calculate the TMEscore. The association between the TMEscore, chemotherapy response, and survival rate was analyzed. Machine learning methods were used to identify key TMEscore-related genes, and a gene signature was constructed to verify the predictive value.ResultsTwo clusters based on the TIIC fraction were identified, and the TMEscore was calculated based on the DEGs of the two clusters. The TMEscore was higher in patients who responded to chemotherapy than in those who did not, and was associated with the survival rate of patients who underwent chemotherapy. Three machine learning methods, support vector machine (SVM), decision tree (DT), and Extreme Gradient Boosting (XGBoost), identified three TMEscore-related genes (ADH1C, SLC26A2, and NANS) associated with the response to chemotherapy. A TMEscore-related gene signature was constructed, and three external cohorts validated that the gene signature could predict the response to chemotherapy. Five datasets and clinical samples showed that the expression of the three TMEscore-related genes was increased in tumor tissues compared to those in control tissues.ConclusionsThe TIIC-based TMEscore was associated with the survival of CRC patients who underwent fluoropyrimidine-based chemotherapy, and predicted the response to chemotherapy. The TMEscore-related gene signature had a better predictive value for response to chemotherapy than for survival.

show abstract

The ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer

Cited by 20 publications

References 54 publications

TAGLN2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of colorectal cancer cells by activating STAT3 signaling through ANXA2

TAGLN2 promotes the proliferation, invasion, migration and epithelial‑mesenchymal transition of colorectal cancer cells by activating STAT3 signaling through ANXA2

Role of EMT in the DNA damage response, double‐strand break repair pathway choice and its implications in cancer treatment

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Contact Info

Product

Resources

About