Moby Dick, one of Herman Melville’s masterpieces, has received tremendous concern for its profound and multiple symbolic and metaphoric meanings. And the pervasive biblical terms and allusions deserve particular attention. This paper, based on Frye's archetypal theory, studies Moby Dick from the perspective of biblical archetypal criticism. The association between the characters and their biblical archetypes helps to reproduce the ancient matrix of The Bible, such as the crime of human beings, themes of sin, the fall, and redemption. The exploration of the biblical archetypal theme in Moby Dick provides us a new perspective to understand the profound significance of the novel. Melville reveals the opposition between good and evil in human beings and shows his contradictory religious outlook as well as his spiritual reflections of his time.
Alternative splicing (AS) of pre-mRNAs is an essential process that regulates gene expression and functional diversity, yet the underlying regulatory mechanisms that control this process during cancer metastasis are not clear. Here, we uncovered that a long non-coding RNA (lncRNA), MIR99AHG, mediates regulation of AS to alter chromatin remodeler function and promote invadopodia formation in colorectal cancer (CRC). We found that MIR99AHG is highly expressed in metastatic CRC cells and patient tissue samples. In vitro and in vivo assays showed that MIR99AHG potently drove CRC cell motility, invasion, and metastasis. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, which cooperatively increased cassette exon inclusion of the chromatin remodeling gene SMARCA1. Mechanistically, MIR99AHG acted as an address label for PTBP1 to fine-tune its binding pattern on SMARCA1 pre-mRNA, thereby controlling the skipping-to-inclusion splicing switch of SMARCA1 and favouring the production of a long isoform (SMARCA1-L). Canonical SMARCA1 was found to suppress cell migration and invasiveness by inhibiting invadopodia formation, but SMARCA1-L was functionally inert. Clinicaldata revealed that MIR99AHG was positively correlated with PTBP1 and SMARCA1-L in human CRC specimens and predicted patient outcome. Furthermore, we showed that the crosstalk with cancer-associated fibroblasts triggers TGF-β/SAMD signalling in CRC cells and activates MIR99AHG expression. Our findings establish a novel mechanism for a lncRNA that interacts with PTBP1 to regulate AS process, providing a potential therapeutic target and predictive biomarker of CRC.
Background Metastasis leads to recurrence and death in colorectal cancer (CRC) patients; however, mechanisms underlying CRC metastasis, especially in its initial stages, remain largely unknown. In this study, we aim to identify long noncoding RNAs (lncRNAs) functionally involved in CRC metastasis initiation and their regulation that could lead to targeted therapeutics. Methods We performed whole transcriptome sequencing using CRC cell lines with divergent spontaneous metastatic properties. The biological roles and mechanisms of lncRNA MIR99AHG were characterized with a series of in vitro and in vivo models and molecular analyses. Results MIR99AHG was upregulated in CRC patients and associated with tumor stage and prognosis. MIR99AHG potently drove migration, invasion and metastasis in CRC cells, and these effects were dependent on its role in promoting invadopodia formation. MIR99AHG interacted with RNA splicing factor PTBP1, which cooperatively modulated alternative splicing of chromatin remodeling gene SMARCA1. Mechanistically, MIR99AHG acted as an address label for PTBP1 to direct its binding to the 5’ splice site of SMARCA1 intron 12, thereby facilitating inclusion of the alternative exon 13 to generate a long isoform (SMARCA1-L). The canonical SMARCA1 inhibited cell migration and invasion and suppressed a core set of genes involved in invadopodia, but the SMARCA1-L was functionally inert in metastasis suppression. Clinically, SMARCA1-L levels were positively correlated with MIR99AHG and PTBP1 in patients with metastatic CRC. Conclusions This study identified that invadopodia was regulated by a splicing switch of SMARCA1 due to the interaction between MIR99AHG and PTBP1, highlighting a novel regulatory mode mediated by lncRNA in alternative splicing of chromatin remodeler during CRC metastasis.
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