Knockdown of hnRNPA1 Promotes NSCLC Metastasis and EMT by Regulating Alternative Splicing of LAS1L exon 9

Abstract

Tumor metastasis is still an insurmountable obstacle in tumor treatment. Lung cancer represents one of the most common malignancies with high morbidity worldwide. hnRNPA1 has been reported to be involved in the regulation of tumor metastasis, while its specific role in tumor metastasis seems to be controversial and its molecular mechanism in lung cancer metastasis remains to be further elucidated. In this study, we confirmed that knockdown of the hnRNPA1 led to enhanced migration, invasion and EMT transition in lung cancer cells. Bioinformatics analysis of the GSE34992 dataset revealed that hnRNPA1 may regulate the alternative splicing (AS) of LAS1L exon 9. Further AGE assays and RIP assays revealed that hnRNPA1 can directly bind to the LAS1L pre-mRNA to inhibit the splicing of LAS1L exon 9. The RNA pull-down assays showed that hnRNPA1 can specifically bind to the two sites (UAGGGU(WT1) and UGGGGU(WT3)) of LAS1L Intron 9. Further Transwell assays indicated that the expression ratio of LAS1L-L/LAS1L-S regulated by hnRNPA1 can further promote the migration, invasion and EMT transition in lung cancer cells. Moreover, hnRNPA1 expression showed significant heterogeneity in lung cancer tissues, which may contain new research directions and potential therapeutic targets. Our results indicate that hnRNPA1 can affect the metastasis of lung cancer cells by modulating the AS of LAS1L exon 9, highlighting the potential significance of hnRNPA1 in lung cancer metastasis.

MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation

“…Interestingly, although several studies have shown that hnRNPA1 can inhibit tumor proliferation and metastasis [ 43 , 46 , 66 – 68 ] and that hnRNPA1 may act as an antitumor factor during tumorigenesis, other studies have reached the opposite conclusion [ 69 – 72 ]. However, in the present study, hnRNPA1 knockdown promoted the growth of AGS and Kato III cells in a manner dependent on the formation of RONΔ160.…”

“…In addition, different reports on the regulatory role of hnRNPA1 in A549 cells have been published. Liu et al reported that hnRNPA1 knockdown inhibited A549 cell growth through cell cycle arrest [ 80 ], and Han et al reported that hnRNPA1 knockdown significantly promoted EMT progression and the metastatic ability of A549 cells through the regulation of alternative splicing via the LAS1L exon 9 skipping event [ 68 ]. It is suggested that hnRNPA1 plays different roles in cancer cells even within the same organ, which is dependent on mRNA splicing.…”

Role of Heterogeneous Nuclear Ribonucleoproteins in the Cancer-Immune Landscape

“…HnRNP induce tumor migration and metastasis through AS ( Figure 3 ). HnRNPA1 enhanced lung cancer metastasis by modulating the splicing of LAS1L exon 9 [ 134 ]. HnRNPA2/B1-induced AS of TP53INP2 inhibited migration in ovarian cancer cell lines [ 101 ].…”

Crosstalk between m6A modification and alternative splicing during cancer progression

“…For example, hnRNPA1's interaction with the flanking exon 9 of PKM leads to an increased skipping of exon 9 and the subsequent up‐regulation of the PKM2 isoform lacking exon 9 77 . However, hnRNPs can also inhibit exon exclusion when binding to exonic regions 78 . Furthermore, SR proteins and hnRNP proteins exhibit antagonistic activities, either promoting or inhibiting splicing 79 .…”

“… 77 However, hnRNPs can also inhibit exon exclusion when binding to exonic regions. 78 Furthermore, SR proteins and hnRNP proteins exhibit antagonistic activities, either promoting or inhibiting splicing. 79 Consequently, modulation of the balance between SR and hnRNP proteins can impact alternative splicing in nuclear speckles.…”