Abstract
BackgroundHypoxic tumors are refractory to DNA damage drugs. However, the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC).MethodsCRC cells were treated with 1% O2 to identify lncRNAs that upregulated under hypoxia. We integrated these lncRNAs with RNA-seq of 4 paired CRC tissues and TCGA data to get candidate lncRNAs. Multiple in vitro and in vivo assays were used to explore the role of LUCAT1 in CRC.ResultsWe identified a hypoxia-induced lncRNA LUCAT1 that facilitated the growth of CRC cells and contributed to drug resistance of CRC cells both in vitro and in vivo. Mechanically, LUCAT1 interacts with polypyrimidine tract binding protein 1 (PTBP1) in CRC cells, facilitates the association of a set of DNA damage related genes with PTBP1, thus resulting in altered alternative splicing of these genes. Moreover, ectopic expression of PTBP1 in CRC cells with knockdown of LUCAT1 abrogated the effects induced by LUCAT1 knockdown. Chemotherapeutics drug combined with LUCAT1 knockdown via antisense oligonucleotides (ASO) would get a better outcome in vivo, compared with group treated with chemotherapeutic drug only. Notably, LUCAT1 is upregulated in CRC tissues, compared to adjacent normal tissues; and CRC patients with higher LUCAT1 have a worse prognosis and poorly responded to chemotherapy in the clinic.ConclusionsOur data suggested CRC cells utilizes LUCAT1 to develop resistance to DNA damage drugs, and disrupting the LUCAT1/PTBP1 axis might be a promising therapeutic strategy for refractory hypoxic tumors.
Highlights
Hypoxic tumors are refractory to DNA damage drugs
Lung cancer associated transcript 1 (LUCAT1) is transcriptionally induced by Hypoxia inducible factor 1 alpha (HIF-1α) under hypoxia To explore the role of hypoxia-induced Long noncoding RNA (lncRNA) in colorectal cancer (CRC), we first treated RKO cell with 1% O2 for 24 h, and found that 552 lncRNAs were upregulated under hypoxia
We integrated these data with the differentially expressed lncRNAs in the cohort of Colon adenocarcinoma (COAD) (Colon Adenocarcinoma) in The Cancer genome atlas (TCGA) and in four paired CRC/ adjacent tissues sequenced by our group, and identified 25 hypoxia-induced lncRNAs that were upregulated in CRC tissues (Fig. 1a and Additional file 1: Table S5)
Summary
Hypoxic tumors are refractory to DNA damage drugs. the underlying mechanism has yet to be elucidated. We aimed to identify lncRNAs that upregulated under hypoxia and their effects on colorectal cancer (CRC). Hypoxia is a common hallmark of solid tumors and contributes to the development and progression of many cancers [1]. Colorectal cancer (CRC) is the third common type of cancers and the leading cause of cancerrelated death worldwide [2]. Huan et al Molecular Cancer (2020) 19:11 across cancer types, and play key roles in cancer development and progression including malignant transformation, cell proliferation, survival, migration and genomic stability [6]. LncRNAs, such as miR31HG, linc-p21, linc-ROR, NEAT1, participate in hypoxia signaling and favor tumor cells to acclimate the hypoxic microenvironment [7,8,9,10]. The role of lncRNAs in hypoxia signaling, in chemoresistance of hypoxic tumor, remains elusive
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