Abstract
Previous study demonstrated that most long non-coding RNAs (lncRNAs) function as competing endogenous RNAs or molecular sponges to negatively modulate miRNA and regulate tumor development. However, the molecular mechanisms of lncRNAs in cancer are not fully understood. Our study describes the role of the lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD). Briefly, we found that, high SPRY4-IT1 expression was associated with aggressiveness and poor outcome in human colorectal, breast and ovarian cancer tissues. In addition, functional assays revealed that SPRY4-IT1 significantly promoted colorectal, breast and ovarian cancer metastasis in vitro and in vivo. Mechanistically, microarray analyses identified several differentially-expressed genes upon SPRY4-IT1 overexpression in HCT 116 colorectal cancer cells. Among them, the 3′-UTR of transcription elongation factor B subunit 1 (TCEB1) mRNA can base-pair with the Alu element in the 3′-UTR of SPRY4-IT1. Moreover, SPRY4-IT1 was found to bind STAU1, promote STAU1 recruitment to the 3′-UTR of TCEB1 mRNA, and affect TCEB1 mRNA stability and expression, resulting in hypoxia-inducible factor 1α (HIF-1α) upregulation, and thereby affecting cancer cell metastasis. In addition, STAU1 depletion abrogated TCEB1 SMD and alleviated the pro-metastatic effect of SPRY4-IT1 overexpression. Significantly, we revealed that SPRY4-IT1 is also transactivated by NF-κB/p65, which activates SPRY4-IT1 to inhibit TCEB1 expression, and subsequently upregulate HIF-1α. In conclusion, our results highlight a novel mechanism of cytoplasmic lncRNA SPRY4-IT1 in which SPRY4-IT1 affecting TCEB1 mRNA stability via STAU1-mediated degradation during cancer metastasis.
Highlights
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death
Our study describes the role of the Long noncoding RNAs (lncRNAs) SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD)
We found that a cytoplasmic lncRNA, namely SPRY4 intronic transcript 1 (SPRY4-IT1), mediated cell metastasis by modulating transcription elongation factor B subunit 1 (TCEB1) mRNA stability via STAU1-mediated mRNA decay (SMD), which in turn increased hypoxia-inducible factor 1α (HIF-1α) expression and promoted the metastasis of cancer cells
Summary
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is a complex process, and many cell-intrinsic elements and extrinsic microenvironmental factors affect the metastatic potential of cancer cells [1]. An enhanced understanding of such process might promote the development of effective metastasis-targeting therapy to improve the overall prognosis of patients with cancer. Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with limited protein coding potential [2]. Whereas most characterized lncRNAs function in the nucleus, much less is known about their mode of action in the cytoplasm. Other known mechanisms associated with lncRNAs in the cytoplasm involve post-transcriptional regulation, which affects mRNA stability or accessibility to the translational machinery [8, 9]
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