Search

Background: Carcinoembryonic antigen (CEA)-related cell adhesion molecule 6 (CEACAM6) is a glycophosphoinositol-anchored glycoprotein which mediates cell-cell interactions. Here, we aimed to explore the specific functions and regulatory mechanisms of CEACAM6 on cisplatin (DDP) in lung adenocarcinoma (LUAD)., Methods: RNA sequencing was performed in the DDP-resistant A549/DDP cell line and parental A549 cell line; miRNA expression profiling of the two cell lines was analyzed using GEO data (GSE43249). Gain- and loss-of-function experiments were used to investigate the biological function of CEACAM6 in vitro. The expression status and prognostic value of CEACAM6 in LUAD were verified using The Cancer Genome Atlas (TCGA) database., Results: CEACAM6 was first screened to be one of the most significantly upregulated genes in the DDP-resistant A549/DDP cell line compared to the parental A549 cell line. Combined with computational prediction of candidate miRNAs that target CEACAM6, miR-146a and miR-26a were selected and verified by qPCR and luciferase reporter assay. The knockdown of CEACAM6 expression in A549/DDP cells inhibited cell proliferation, invasion and migration, decreased the IC 50 values of DDP, and caused a significant downregulation of N-cadherin, vimentin, Sox2, Oct4 and GTP-RhoA and upregulation of E-cadherin; while CEACAM6 overexpression in A549 cells resulted in the opposite effects. Of note, both miR-146a and miR-26a could counteract the biological effects of CEACAM6. Furthermore, CEACAM6 mRNA expression was significantly unregulated in DDP-resistant LUAD tissues of TCGA database., Conclusions: CEACAM6 promotes DDP resistance in LUAD by affecting the epithelial-mesenchymal transition (EMT) phenotype and stemness, which is post-transcriptionally regulated by miR-146a and miR-26a., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Acquired resistance remains a key challenge in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) therapy in lung adenocarcinoma (LUAD). Recent studies have shown that Notch signaling is associated with drug resistance. However, its role and possible mechanisms in EGFR-TKI resistance are not yet clear. In our study, we found that among four members of NOTCH1-4, only NOTCH3 was upregulated in LUAD tissues and TKI-resistant cell line (HCC827GR6). Knockdown of NOTCH3 by siRNA significantly inhibited proliferative ability, and decreased colony and sphere formation in HCC827GR6 cells. Then miR-150 was identified as a posttranscriptional regulator of NOTCH3. Its expression was downregulated in LUAD tissues and negatively correlated with NOTCH3 mRNA. The cell proliferation and IC 50 of gefitinib were decreased in HCC827GR6 cells transfected with miR-150 mimic, but was reversed when cotransfected with NOTCH3 overexpressed vector. Moreover, we also enrolled 20 patients with advanced LUAD who have taken TKIs as first-line therapy in this study. We found that collagen 1A1 (COL1A1) expression was increased significantly in LUAD tissues both at mRNA and protein levels, and positively correlated with NOTCH3 expression verified in our data and TCGA data. Univariate survival analysis showed that patients with high protein expression of NOTCH3 or COL1A1 were associated with shorter overall survival (OS). Taken together, these results suggest that miR-150/NOTCH3/COL1A1 axis contributed to EGFR-TKI resistance in LUAD, which provide a potential therapeutic target for LUAD treatment.

Long non-coding RNA small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) is located on chromosome 1q23.2, and has been suggested to serve as oncogenic lncRNA in many kinds of human malignancy. The role of SUMO1P3 in non-small cell lung cancer (NSCLC) was still unknown. In our study, we analyzed The Cancer Genome Atlas (TCGA) database, and observed SUMO1P3 expression was increased in both lung squamous cell carcinoma and lung adenocarcinoma. Then, we confirmed that SUMO1P3 expression was significantly increased in NSCLC cancer tissues and cell lines. Meanwhile, the expression levels of SUMO1P3 expression in metastatic lymph node specimens were strikingly elevated in comparison to primary NSCLC tissue specimens. Then, we found high SUMO1P3 expression was correlated with late clinical stage, lymph node metastasis, distant metastasis and poor differentiated degree. In the survival analysis of TCGA, we observed that SUMO1P3 expression had no association with overall survival and disease free survival in NSCLC patients. There was a statistically negative correlation between SUMO1P3 expression and miR-136 expression in NSCLC tissues. Moreover, miR-136 directly bound to SUMO1P3, and SUMO1P3 negatively regulated miR-136 expression in NSCLC cells. Furthermore, SUMO1P3 promoted NSCLC cell migration and invasion via regulating miR-136. In conclusion, SUMO1P3 functions as metastasis-associated lncRNA in NSCLC., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ultraviolet radiation resistance‑associated gene (UVRAG) regulates autophagy by promoting the formation and maturation of autophagosomes. The aim of the present study was to investigate the effects of UVRAG and UVRAG‑targeting miRNA on the regulation of autophagy and apoptosis in gastric cancer (GC). TargetScan was used to predict that miR‑183 targets the 3'‑untranslated region (UTR) of UVRAG, while the interaction between miR‑183 and the 3'‑UTR of UVRAG was assessed using a dual luciferase reporter assay. Autophagy was induced in the GC cell line MKN28 by serum starvation. miR‑NC mimics, miR‑183 mimics, miR‑NC inhibitors and miR‑183 inhibitors were transfected into MKN28 cells, followed by assessment of the UVRAG expression, cell viability and cell apoptosis by western blotting, reverse transcription‑quantitative polymerase chain reaction, Cell Counting Kit‑8 and flow cytometry, respectively. It was demonstrated that autophagy resulted in miR‑183 downregulation and overexpression of UVRAG mRNA and protein in MKN28 cells. Transfection with miR‑183 mimic or inhibitor affected the expression of miR‑183 and, consequently, UVRAG. miR‑183 overexpression reversed the starvation‑induced inhibition of cell proliferation, while inhibition of miR‑183 reduced the proliferation of GC cells. miR‑183 overexpression reversed starvation‑induced apoptosis, while miR‑183 inhibition promoted starvation‑induced apoptosis in GC cells. Finally, miR‑183 overexpression attenuated starvation‑induced autophagy (LC‑3), apoptosis (Bax/Bcl‑2) and UVRAG expression, while miR‑183 inhibition exerted the opposite effects. In conclusion, the results of the present study indicated that miR‑183 inhibits starvation‑induced autophagy and apoptosis by targeting UVRAG in human GC cells.

Recently, circular RNA (circRNA) is identified as a novel class of noncoding RNA with important roles in human diseases, such as cancer. However, how circRNA participates in colorectal cancer (CRC) remains unclear. In this study, we aimed to illustrate the role of circ_0026344 in CRC progression. We showed that circ_0026344 expression was downregulated in CRC tissues compared to adjacent normal tissues. Moreover, the level of circ_0026344 was inversely correlated with CRC advance and lymphoid node metastasis. Additionally, circ_0026344 low expression predicted poor prognosis in CRC patients. We identified circ_0026344 as a miRNA sponge for microRNA-21 (miR-21) and microRNA-31 (miR-31) whose expression levels were elevated in CRC tissues. And the level of circ_0026344 was reversely correlated with both miR-21 and miR-31 levels in CRC tissues. Functionally, we found that ectopic expression of circ_0026344 decreased the growth and invasion of CRC cells while promoting apoptosis in vitro. The xenograft experiment indicated that circ_0026344 overexpress led to CRC growth inhibition in vivo. Rescue assays further demonstrated that circ_0026344 exerted biological functions by sponging miR-21 and miR-31 in CRC. In conclusion, this study revealed that circ_0026344/miR-21/miR-31 regulatory signaling was implicated in CRC progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Lung cancer characterized with malignant cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa_circRNA_103809 in lung cancer tissues. We showed hsa_circRNA_103809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa_circRNA_103809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa_circRNA_103809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa_circRNA_103809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa_circRNA_103809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa_circRNA_103809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)