Abstract
BackgroundColorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related death worldwide. Increasing evidence indicates that the deregulation of long noncoding RNAs (lncRNAs) contributes to tumor initiation and progression; however, little is known about the biological role of cancer susceptibility candidate 9 (CASC9) in CRC.MethodsNovel lncRNAs potentially involved in CRC tumorigenesis were identified from datasets downloaded from The Cancer LncRNome Atlas and The Atlas of Noncoding RNAs in Cancer. The CRC cell lines HCT-116, HCT-116 p53−/−, SW620, SW480, HT-29, LoVo, LS-174T, and RKO were used. Colony-formation, MTS, cell-cycle, apoptosis, and in-vivo tumorigenesis assays were used to determine the role of CASC9 in CRC cell growth in vitro and in vivo. Potential interaction between CASC9 and cleavage and polyadenylation specificity factor subunit 3 (CPSF3) was evaluated using RNA immunoprecipitation and RNA-protein pull-down assays. RNA-sequencing was performed to analyze gene expression following CASC9 knockdown. RT-qPCR, western blotting, and mRNA decay assays were performed to study the mechanisms involved.ResultsCASC9 was frequently upregulated in CRC, which was correlated with advanced TNM stage, and higher CASC9 levels were associated with poor patient outcomes. Knockdown of CASC9 inhibited growth and promoted apoptosis in CRC cells, whereas ectopic CASC9 expression promoted cell growth in vitro and in vivo. We demonstrated that CPSF3 is a CASC9-interacting protein, and knockdown of CPSF3 mimicked the effects of CASC9 knockdown in CRC cells. Furthermore, we found that CASC9 exerts its oncogenic activity by modulating TGFβ2 mRNA stability and upregulating the levels of TGFβ2 and TERT, resulting in an increase in phosphorylated SMAD3 and activation of TGF-β signaling, and enhanced TERT complex function in CRC cells. Finally, CPSF3 was significantly upregulated in CRC tissues as compared with adjacent or non-adjacent normal colon tissues, and CASC9, CPSF3, and TGFβ2 levels in human CRC tissues were positively correlated.ConclusionsCASC9 is a promising prognostic predictor for patients with CRC and the CASC9-CPSF3-TGFβ2 axis is a potential therapeutic target for CRC treatment.
Highlights
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancerrelated death worldwide
LncRNA cancer susceptibility candidate 9 (CASC9) is frequently upregulated in CRC To identify novel Long non-coding RNA (lncRNA) involved in CRC tumorigenesis, we downloaded lncRNA expression data for colon adenocarcinoma (COAD) (860 dysregulated lncRNAs, including 498 upregulated and 362 downregulated lncRNAsin COAD; fold change ≥2 or ≤ 0.5, P < 0.05) and clinical survival data (104 lncRNAs with significant prognostic value, log-rank P < 0.05) from The Cancer LncRNome Atlas (TCLA) and The Atlas of Noncoding RNAs in Cancer (TANRIC) [29], respectively
Our data indicate that CASC9 acts as an oncogene in CRC and significantly promotes CRC cell growth in vitro and in vivo
Summary
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancerrelated death worldwide. Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related death worldwide [1,2,3]. As in many other solid tumors, sequential genetic and epigenetic changes in specific oncogenes and/or tumor suppressor genes can induce CRC onset, progression, and metastasis [4]. Very early diagnosis and personalized care, as well as a better knowledge of the molecular basis of disease onset and progression are crucial to developing a cure for CRC. A better understanding of the mechanisms that drive the disease and the identification of novel therapeutic targets are priorities for improving CRC treatment. The majority of lncRNAs are expressed in a highly tissue- and cell typespecific manner [7, 8] and are potentially efficacious targets for systemic cancer treatment [9]
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