The novel role of LOC344887 in the enhancement of hepatocellular carcinoma progression via modulation of SHP1-regulated STAT3/HMGA2 signaling axis

Pseudogene-derived long non-coding RNAs (lncRNAs) have become crucial regulators in cancer progression. Extensive research highlights the pivotal role of signal transducer and activator of transcription 3 (STAT3) in promoting hepatocellular carcinoma (HCC) progression. As a result, targeting aberrant STAT3 activation presents a promising therapeutic strategy for HCC. Our study aims to identify the key pseudogene-derived lncRNA involved in modulating STAT3 activation and driving HCC progression. Our study is the first to identify a significant upregulation of LOC344887, a pseudogene-derived lncRNA, in HCC tissues. Elevated LOC344887 levels correlated with poor overall survival (OS) and recurrence-free survival (RFS), highlighting its potential as a biomarker for HCC. The rapid amplification of cDNA ends (RACE) and RT-PCR experiments revealed the expression of a novel LOC344887 transcript, named LOC344887-v2, alongside the annotated RefSeq transcript NR_151491 (LOC344887-v1) in both HCC tissues and hepatoma cell lines. Functional assays demonstrated that LOC344887 enhances cellular migration and invasion, with its variant LOC344887-v2 exhibiting a more pronounced effect. Further, LOC344887 mechanistically regulates STAT3 phosphorylation at tyrosine 705, which is crucial for maintaining STAT3 activation in HCC. Our findings unravel that LOC344887 not only physically interacts with p-STAT3 but also prevents its dephosphorylation by src homology region 2 domain-containing phosphatase 1 (SHP-1), thereby sustaining oncogenic signaling. In addition, we identified HMGA2 as a target of the LOC344887/SHP-1/STAT3 axis, with higher HMGA2 expression correlating with poorer prognosis in HCC patients. The ability of LOC344887 to regulate HMGA2 through direct binding of STAT3 to its promoter underlines its role in HCC progression. Collectively, these findings elucidate a novel oncogenic role of LOC344887 in HCC and suggest that targeting this lncRNA and its associated pathways may provide novel therapeutic strategies for improving patient outcomes in HCC.