Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α.

Long non-coding RNAs (lncRNAs) are emerging as key molecules in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression and functions of lncRNAs in the development of colorectal cancer (CRC). LncRNA expression profiling of CRC, adenoma and normal colorectal tissues was performed to identify tumour-related lncRNAs involved in colorectal malignant transformation. Then, we used quantitative reverse transcription PCR assays to measure the tumour-related lncRNA and to assess its association with survival and response to adjuvant chemotherapy in 252 patients with CRC. The mechanisms of CCAL function and regulation in CRC were examined using molecular biological methods. We identified colorectal cancer-associated lncRNA (CCAL) as a key regulator of CRC progression. Patients whose tumours had high CCAL expression had a shorter overall survival and a worse response to adjuvant chemotherapy than patients whose tumours had low CCAL expression. CCAL promoted CRC progression by targeting activator protein 2α (AP-2α), which in turn activated Wnt/β-catenin pathway. CCAL induced multidrug resistance (MDR) through activating Wnt/β-catenin signalling by suppressing AP-2α and further upregulating MDR1/P-gp expression. In addition, we found that histone H3 methylation and deacetylases contributed to the upregulation of CCAL in CRC. Our results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression.

Ma Y ，Yang Y ，Wang F ，Moyer MP ，Wei Q ，Zhang P ，Yang Z ，Liu W ，Zhang H ，Chen N ，Wang H ，Wang H ，Qin H ... -  《-》

Long non-coding RNA CCAL promotes hepatocellular carcinoma progression by regulating AP-2α and Wnt/β-catenin pathway.

Long non-coding RNAs are emerging as key molecules in cancer progression. LncRNA-CCAL has shown to be highly expressed and important in regulating CRC and osteosarcoma development. Nevertheless, the expression and mechanism of CCAL in HCC is still not well understood. qRT-PCR and ISH were used to evaluate CCAL expression in HCC tissues and cell lines. Histone H3 methylation and acetylation levels across CCAL promoter region were examined by chromatin immunoprecipitation assays. Transfection of Lv-CCAL-shRNAs into HCC cell lines was used to evaluate cellular invasion and proliferation. The influence of CCAL depletion on AP-2α expression and Wnt/β-catenin pathway was analyzed by qRT-PCR, western blot and immunofluorescence. Higher expression of CCAL was found in HCC tumor tissues compared with normal tissues, and was associated with tumor metastasis and TNM stage. Furthermore, the decreased histone H3 methylation and increased histone H3 acetylation across CCAL promoter region contributed to the upregulation of CCAL in HCC. Moreover, the depletion of CCAL inhibited HCC cellular invasion and proliferation, and promoted cell apoptosis. In addition, CCAL depletion up-regulated AP-2α expression and inhibited Wnt/β-catenin pathway activation. CCAL has an important role in hepatic carcinogenesis and may serve as a new target for HCC diagnosis and treatment.

Liu Y ，Yang Y ，Wang T ，Wang L ，Wang X ，Li T ，Shi Y ，Wang Y ... -  《-》

Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells.

Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long-standing recognition of the crosstalk between carcinoma-associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer-associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA-ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β-catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.

Deng X ，Ruan H ，Zhang X ，Xu X ，Zhu Y ，Peng H ，Zhang X ，Kong F ，Guan M ... -  《-》

LncRNA SLCO4A1-AS1 facilitates growth and metastasis of colorectal cancer through β-catenin-dependent Wnt pathway.

Yu J ，Han Z ，Sun Z ，Wang Y ，Zheng M ，Song C ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Long noncoding RNA HNF1A-AS1 indicates a poor prognosis of colorectal cancer and promotes carcinogenesis via activation of the Wnt/β-catenin signaling pathway.

Long non-coding RNAs (lncRNAs) have been identified to play critical roles in tumorigenesis. LncRNA HNF1A-AS1 has been suggested to act as an oncogene and serves as a novel prognostic biomarker for various cancer. However, the biological role and clinical significance of lncRNA HNF1A-AS1 in colorectal cancer (CRC) have yet to be fully elusive. Therefore, the present study was designed to determine the expression of lncRNA HNF1A-AS1 in patients with CRC, the role of lncRNA HNF1A-AS1 in CRC cells, as well as the underlying regulatory mechanisms. Our results indicated that the expression of lncRNA HNF1A-AS1 was significantly upregulated in both CRC tumor tissues and CRC cell lines in comparison with adjacent non-tumor tissues and the human normal colonic epithelial cell line (HcoEpiC). The Kaplan-Meier survival analysis further suggested that high expression of lncRNA HNF1A-AS1 might be an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in patients with CRC. Moreover, the area under the receiver operating characteristic (ROC) curve for HNF1A-AS1 was up to 0.8714, implying that HNF1A-AS1 had diagnostic significance as it could discriminate tumor tissues from nontumorous tissues. In addition, silencing of lncRNA HNF1A-AS1 abrogated the proliferation of CRC cells by MTS assay and clonogenic assay, arrested cell cycle at G0/G1 stage and reduced the migration and invasion in CRC cells. Finally, we found that decreased expression of lncRNA HNF1A-AS1 suppressed the Wnt/β-catenin signaling pathway activity by downregulating the expression of β-catenin,cyclinD1, and c-myc. In conclusion, these findings provide evidence that lncRNA HNF1A-AS1 may be considered as a new prognostic biomarker and therapeutic target in patients with CRC.

Zhang X ，Xiong Y ，Tang F ，Bian Y ，Chen Y ，Zhang F ... -  《-》