LINC01106 Drives Colorectal Cancer Growth and Stemness Through a Positive Feedback Loop to Stimulate Hedgehog Activation

Abstract

Background: From prior works, aggressive tumor cell growth, stemness, migration, and invasion are related to oncogenesis. Long non-coding RNA LINC01106 is overexpressed and decreases overall survival time of COAD (Colon adenocarcinoma) patients, as annotated in bioinformatics website GEPIA. Therefore, the study is to define the unclear biological function of LINC01106 in CRC (colorectal cancer). Methods: qRT-PCR, FISH and subcellular fractionation probed LINC01106 expression and distribution in CRC cells. CRC cell growth was determined in the absence of LINC01106 via EdU and colony formation. The effects of LINC01106 on CRC migration, invasion and EMT were monitored using transwell assay and western blot. Stemness of CRC cells was examined via sphere formation. LINC01106-mediated mechanism was monitored via ChIP, luciferase reporter, RNA pull-down followed by silver staining, and RIP assays. Results: Our data supported that LINC01106 induced malignant proliferation and stem-like phenotypes in CRC cells. Mechanistically, cytoplasmic LINC01106 sponged and suppressed miR-449b-5p in CRC cells. Moreover, online data showed that LINC01106 was positively correlated with Gli4 level in COAD tissues. Gli4 elevation predicted dreadful survival of COAD patients. Mechanical assays confirmed that LINC01106 could increase Gli4 expression as a miR-449b-5p sponge. Furthermore, nuclear LINC01106 interacted with FUS to Gli1 and Gli2 promoters for Gli1 and Gli2 transcriptional elevation, resulting in Hedgehog signaling transduction. Intriguingly, Gli2 was a transcription initiator of LINC01106. Rescue experiments elaborated that Gli1, Gli2, Gli4, and Hedgehog pathway agonist SAG could antagonize LINC01106-modulated CRC growth aggressiveness, and stemness. Rescue experiments confirmed LINC01106-mediated intermolecular functions in CRC growth and stemness. Conclusion: Previously unrecognized LINC01106 was functionally and mechanically characterized in CRC. It introduced that Gli2-induced LINC01106 could aggravate CRC progression through post-transcriptional or transcriptional promotion of Gli family proteins. It is expected to impart innovative avenues for generating CRC therapeutic approaches. Funding Statement: This work was supported by Jiangsu Provincial Natural Science Fund (BK20151017), The Six Major Talent Peak Project of Jiangsu Province (class C, NO WSW-050) and the Young Talents Program of Jiangsu Cancer Hospital (QL201816). Declaration of Interests: The authors stated: None. Ethics Approval Statement: The authors stated: Not applicable.