The long non-coding RNA HOTAIRM1 suppresses cell progression via sponging endogenous miR-17-5p/ B-cell translocation gene 3 (BTG3) axis in 5-fluorouracil resistant colorectal cancer cells.

5-Fluorouracil (5-FU)-based chemotherapy has always been the first-line treatment of colorectal cancer (CRC). However, the occurrence of clinical 5-FU resistance is a major reason for CRC therapy failure. This study intended to explore the possible role of long non-coding RNA HOTAIRM1 (HOTAIRM1) in the pathogenesis of 5-FU resistant CRC and its underlying mechanism. Our data showed that HOTAIRM1 was downregulated in CRC tissues and cell lines (HCT116 and SW480), and even lower in 5-FU resistant CRC tissues and cell lines (HCT116/5-FU and SW480/5-FU). In vitro, effects of HOTAIRM1 dysregulation in 5-FU resistant CRC cells were investigated and its overexpression could reduce cell viability, invasion, migration, and multi-drug resistance as evidenced by MTT assay, Transwell assay, epithelial-mesenchymal transition (EMT), and western blot analyzing expression of drug-resistant genes MRP1 and MDR1, respectively. Mechanically, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) identified that HOTAIRM1 and B-cell translocation gene 3 (BTG3) were target genes of miR-17-5p. Moreover, miR-17-5p was upregulated and BTG3 was downregulated in HCT116/5-FU and SW480/5-FU cells. Silencing of miR-17-5p showed suppressive role on cell viability, invasion, migration, and multi-drug resistance in HCT116/5-FU and SW480/5-FU cells, which could be abolished by HOTAIRM1 knockdown. Similarly, ectopic expression of miR-17-5p reversed BTG3-mediated inhibition on cell viability, invasion, migration, and multi-drug resistance. In vivo, the tumorigenesis of HCT116/5-FU cells when highly expressed HOTAIRM1 by lentivirus infection was inhibited through downregulating miR-17-5p and upregulating BTG3. In conclusion, HOTAIRM1 might act as a tumor-suppressor in 5-FU resistant CRC cells in vitro and in vivo through downregulating miR-17-5p/BTG3 pathway and inhibiting multi-drug resistance.

Circulating tumor cells predict prognosis following secondline AZD 9291 treatment in EGFR-T790M mutant non-small cell lung cancer patients.

PURPOSE: AZD9291 has been developed as third-generation epithermal growth factor receptor (EGFR)- tyrosine kinase inhibitor (TKI) with activities against T790M mutation. This study aimed to isolate and quantify the circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) patients after first-line EGFR TKIs and investigate their role in providing prognostic information. METHODS: Enrolled patients confirmed with EGFR T790M mutation received AZD9291 80 mg orally once daily as second-line treatment. Serial blood samples were taken at baseline (CTC-d0) and on day 28 (CTC-d28) following the initiation of AZD9291 for detection of CTCs using the Cell-Search system. RESULTS: The CTC measurements were dichotomized as favorable (<5 CTCs) and unfavorable (≥5 CTCs) groups. Patients in the favorable group at baseline exhibited significantly longer median progression-free survival (PFS) compared with patients in the unfavorable group (9.3 vs. 6.5 months; p=0.0002). The PFS interval for patients in the favorable group on day 28 was 9.7 months, significantly longer than the median PFS time of 6.2 months achieved by patients in the unfavorable group (p=0.011). In univariate and multivariate analysis, CTC-d0 ≥5 vs CTC-d0=0-4 was significantly associated with poor PFS. CONCLUSIONS: This is the first report over the presence of CTCs and their prognostic role in patients with EGFR T790M-positive NSCLC following disease progression on an EGFR TKI. The use of serial CTC evaluation as a surrogate biomarker needs further validation in larger samples of patients.

Circulating Tumor Cells Predict Prognosis Following Tyrosine Kinase Inhibitor Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Patients.

Epithelial growth factor receptor (EGFR) mutations are present in 10%-26% of non-small cell lung cancer (NSCLC) tumors and are associated with the response to tyrosine kinase inhibitors (TKIs). This study aimed to detect and quantify the presence of circulating tumor cells (CTCs) in EGFR-mutant NSCLC patients and investigate their possible role in providing prognostic information. Enrolled patients received erlotinib (150 mg) or gefitinib (250 mg) orally once daily as the first-line treatment. Serial blood samples were taken at baseline (CTC-d0) and on day 28 (CTC-d28) following the initiation of erlotinib/gefitinib for detection of CTCs using the CellSearch system. CTCs ≥2 were found in 47/107 (44%) and CTCs ≥5 in 17/107 (15%). The CTC measurements were dichotomized as favorable (<5 CTCs) and unfavorable (≥5 CTCs) groups. The median progression-free survival (PFS) interval for patients in the favorable group at baseline was 11.1 months, significantly longer than the median PFS time of 6.8 months achieved by patients in the unfavorable group (p = 0.009). Patients in the favorable group on day 28 exhibited significantly longer PFS compared with patients in the unfavorable group (11.6 vs. 6.3 months; p < 0.0001). In univariate analysis, CTC-d0 ≥ 5 versus CTC-d0 = 0-4 was significantly associated with poor PFS and time-to-treatment failure (TTF). CTC-d28 ≥ 5 versus CTC-d28 = 0-4 was significantly associated with a poor PFS outcome. CTC-d0 and CTC-d28 remained independent poor prognostic markers in the stepwise multivariate analysis. Our study indicates that the CTC count is a prognostic factor for PFS and TTF outcomes in patients with advanced EGFR-mutant NSCLC.

MiR-205 in cancer: an angel or a devil?

MicroRNAs (MiRNAs) are small non-coding RNAs that regulate their target genes expression at the post-transcriptional level. As accumulating properties of miR-205 have been identified, complex roles of miR-205 in tumor initiation and progression are emerging. MiR-205 acts either as a tumor suppressor through inhibiting proliferation and invasion, or as an oncogene through facilitating tumor initiation and proliferation, depending on the specific tumor context and target genes. In this review, we focus on the properties of miR-205 in cancers to shed light on better management of various fatal malignancies. Moreover, we discuss epigenetics that may account for the fluctuation of miR-205 expression. In addition, we sketch a network of miR-205 and its targets to further elucidate the mechanisms through which miR-205 exerts its multiple functions.