Reduced Let-7a Is Associated with Chemoresistance in Primary Breast Cancer

Wu, Jiarui; Li, Shunrong; Jia, Weijuan; Deng, Heran; Chen, Kai; Zhu, Liling; Yu, Fang; Su, Fengxi

doi:10.1371/journal.pone.0133643

Cited by 38 publications

(33 citation statements)

References 16 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alterations of this miRNA in our study were similar to those described in the literature earlier by our group as well as by other investigators [22,23,40–42]. The aberrant expression of let-7a in many types of human cancers including PC indicates its tumor suppressor role [22,24,43,44]. For example, over-expression of let-7a with diflourinated-curcumin (CDF) mediated tumor regression with reduced EZH2, Notch-1, and EpCAM expression in PC in our previous study [22].…”

Section: Discussionsupporting

confidence: 90%

Differential Expression of Micrornas in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer

et al. 2015

View full text Add to dashboard Cite

Objective Pancreatic cancer (PC) is a lethal disease with disappointing results from current treatment modalities, suggesting that novel therapeutic strategies are urgently needed. Since microRNAs (miRNAs) are important player in biology, the clinical utility of miRNAs for designing novel therapeutics is an active area of research. The objective of the present study was to examine differentially expressed miRNAs between normal and tumor tissues, and in plasma samples obtained from PC patients, chronic pancreatitis (CP) patients and healthy subjects (HC). Material and methods The miRNA expression profiling using formalin-fixed paraffin embedded (FFPE) tissues from normal and tumor specimens was accomplished using miRBase version 19 (LC Sciences, Houston, TX, USA). Quantitative real-time PCR (qRT-PCR) was subsequently performed in individual samples for 7 selected miRNAs. In addition, qRT-PCR was also performed for assessing the expression of 8 selected miRNAs in plasma samples. Results A significant difference in the expressions of miR-21, miR-205, miR-155, miR-31, miR-203, miR-214 and miR-129-2 were found in tumor tissue samples. Lower expression of miR-214 was found to be associated with better overall survival. We also observed differential expression of 8 miRNAs in plasma samples of CP and PC patients compared to HC. Interestingly, over expression of miR-21, and miR-31 was noted in both tumor tissues and in the plasma. Conclusion We found deregulated expression of miRNAs that could distinguish normal from PC in two different types of samples (tissues and plasma). Interestingly, lower expression of miR-214 was found to be associated with better overall survival. Although not statistically significant, we also observed higher expression of let-7a and lower expression of miR-508 to be associated with overall better survival. We conclude that our study nicely lays the foundation for detailed future investigations for assessing the role of these miRNAs in the pathology of pancreatic cancer.

show abstract

Section: Discussionsupporting

confidence: 90%

Differential Expression of Micrornas in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Furthermore, emerging evidence has demonstrated that members of the let-7 family of miRNAs are downregulated in a number of types of human cancer, and that low let-7 expression has been correlated with resistance to chemotherapeutics (37,38). Downregulation of let-7 was also associated with chemoresistance in breast cancer cells (39). In addition, Sugimura et al (38) reported that low expression of let-7b and let-7c was significantly associated with a poor response to chemotherapy in esophageal squamous cell carcinoma, and that transfection of let-7c restored sensitivity to cisplatin and increased the rate of apoptosis following exposure to cisplatin in vitro assays.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

et al. 2018

View full text Add to dashboard Cite

Abstract. Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let-7f-5p expression was elevated in chemotherapy-resistant CRC tissues compared with chemotherapy-sensitive tissues. Furthermore, upregulating let-7f-5p increased the expression levels of the anti-apoptotic proteins, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and decreased the activity of caspase-3 and caspase-9 in CRC cells. By contrast, downregulating let-7f-5p yielded the opposite effect. Notably, the results indicated that let-7f-5p promoted chemotherapeutic resistance by directly repressing the expression of several pro-apoptotic proteins, including tumor protein p53, tumor protein p53-inducible nuclear protein 1, tumor protein p53-inducible nuclear protein 2 and caspase-3. Therefore, a novel mechanism by which let-7f-5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let-7f-5p may become an effective therapeutic strategy against CRC. IntroductionColorectal cancer (CRC) is one of the most prevalent causes of cancer-associated mortality worldwide (1,2). Clinically, 5-fluorouracil (5-FU)-based chemotherapy serves as the initial first-line chemotherapeutic drug of choice in patients with CRC; however, the response rates to 5-FU are ~15% in patients with advanced CRC (3). Although novel therapeutic approaches, including combination chemotherapy of 5-FU and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), have presented promising potential, the majority of the patients continue to exhibit inadequate responses (4,5). The failure of chemotherapy in CRC patients is primarily attributed to therapeutic resistance following a long period of treatment (6). These observations emphasize that chemotherapeutic resistance is a major obstacle in the treatment of CRC, and that the molecular mechanisms underlying this issue remain unclear.Chemotherapeutic resistance poses a major challenge in cancer chemotherapy. Chemoresistance of tumor cells develops primarily due to acquired resistance de novo, following an initially sensitive response, and/or in combination with pre-established cell-intrinsic mechanisms (7). A number of well-established mechanisms are reported to be involved in cancer drug resistance, including failure of the drug to reach or enter the target cell, formation of efflux pumps on the surface of tumor cells, increased expression of anti-apoptotic proteins, induction of drug-detoxifying mechanisms and upregulation of DNA repair enzymes (8,9). However, there is an absence of integral understanding of acquired drug resistance in the context of CRC. Such insight may be crucial for the

show abstract

“…Let-7a, a member of microRNA let-7 family, has been linked to various cancer types, e.g., breast cancer, non small cell lung cancer (NSCLC), pancreatic cancer, colon cancer [19-22]. It has been reported that overexpression of let-7a could sensitize resistant breast cancer cells to epirubicin in vitro [22].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that overexpression of let-7a could sensitize resistant breast cancer cells to epirubicin in vitro [22]. In some studies, let-7a has been shown to inversely correlate with well-known oncogenes, including HMGA2[23], and positively regulate classical apoptosis-related gene CASP3[24].…”

Section: Introductionmentioning

confidence: 99%

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2

Xiao

Wang

2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Pancreatic cancer cells (PCC) is one of the most risky cancers and gemcitabine (GEM) is the standard first-line drug for treating PCC. The PCC will develop drug resistance to GEM after a period of treatment. However, the detailed molecular mechanism of pathogenesis and drug resistance remains unresolved. Methods: we employed qRT-PCR and western blot to examine the expression level of CXCR4, let-7a and HMGA2. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The expression level of epithelial marker E-cadherin and mesenthymal marker N-cadherin was detected by western blot. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. Results: we first proved that CXCR4 negatively regulated let-7a in PCC. Next, let-7a was confirmed to play crucial role in tumorigenesis, metastasis and drug resistance of pancreatic cancer cells Bxpc-3 and Panc-1 in vitro and in vivo. Finally, we identified HMGA2 as important downsteam target of let-7a in PCC and overexpression of HMGA2 restores cell proliferation, metastasis and chemosensitivity of GEM inhibited by let-7a. Conlusion: Taken together, we show an important signaling pathway involved in pathogenesis and drug resistance of PCC, thereby providing deeper insight into molecular mechanism by which CXCR4/let-7a regulates tumorigenesis and drug resistance of PCC. These findings will help us develop new strategies for diagnosis and treatment of PCC.

show abstract

Reduced Let-7a Is Associated with Chemoresistance in Primary Breast Cancer

Cited by 38 publications

References 16 publications

Differential Expression of Micrornas in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer

Differential Expression of Micrornas in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

CXCR4/Let-7a Axis Regulates Metastasis and Chemoresistance of Pancreatic Cancer Cells Through Targeting HMGA2

Contact Info

Product

Resources

About