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Tumor Discovery LncRNA HA117 in osteosarcoma regulation

GO analysis showed significant enrichment of specific pathway, such as PTPN1, MAP3K1, MTOR, and CD28. The
terms for HA117 target genes. Their proteins are primarily PTPN1 is a tumor marker up-regulated in various cancers,
located in the intracellular region, including the cytoplasm associated with cancer immunity and drug sensitivity.
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(GO:0005737, 31 genes), cytosol (GO:0005829, 32 genes), MAP3K1, also known as MEKK1, encodes a serine/
and nucleus (GO:0005634, 31 genes). In agreement with threonine kinase involved in the MAPK signaling pathway
the protein locations, GO molecular function annotation and is related to the progression of breast cancer. 52,53 The
found that 60 target genes of HA117 are mainly related to MTOR gene encodes a serine/threonine protein kinase, a
protein binding (GO:0005515). Unlike cellular component component of two distinct complexes: mTOR complex 1
and molecular functional enrichment, the target genes of and mTOR complex 2, which control protein synthesis,
HA117 are diverse in their biological processes. They play cell growth, proliferation, and actin cytoskeleton, thereby
key roles in the negative regulation of apoptotic processes promoting cell survival and cell cycle progression.
(GO:0043066), apoptotic signaling pathways (GO:0097190), Recent findings indicate that the activation of mTOR is
response to endoplasmic reticulum stress (GO:0034976), associated with osteosarcoma cell growth, proliferation,
and response to viruses (GO:0009615). In addition, and metastasis. In addition, Li et al. confirmed that the
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GO term enrichment analysis (P < 0.05) revealed some CD86/CD28 co-stimulatory signal enhances prognosis in
interesting results, such as the enrichment of 17 genes in the osteosarcoma by influencing the activation of memory CD4
extracellular exosome (GO:0070062). Previous studies have T-cells. These findings suggest that HA117 may interfere
demonstrated a strong correlation between exosomes and with immune signaling pathways related to osteosarcoma
key processes in malignant tumors, including tumorigenesis, chemotherapy by regulating these target genes.
metastasis, drug resistance, angiogenesis, and modulation of
immune responses. 41-43 Sha et al. reported that the Hic-5 In this study, we primarily predicted the distal target
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gene, mediated by exosomes, can regulate the proliferation genes regulated by HA117 by analyzing the correlation
and apoptosis of osteosarcoma cells through the Wnt/β- between HA117 and mRNA. However, due to the limited
catenin signaling pathway. Jiang et al. reported that sample size, the predicted results of gene–gene interaction
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exosome-mediated delivery of has-miR-144-3p promotes relationships often have a high rate of false positives.
ferroptosis, thereby inhibiting the proliferation, migration, Therefore, we also used LncTar software to predict the
and invasion of osteosarcoma cells through the regulation of target genes of HA117, as it can predict the best binding
ZEB1. Among the 17 exosome-related genes, RPS9, NME2, sites based on the complementary matching relationship
and ADAM9 have been implicated in the progression of between sequences and the calculation of minimum
osteosarcoma. RPS9, a protein that interacts with NPM1, is free energy. Relying on a single method may introduce
notable for being one of the first identified proteins to directly technical flaws; thus, combining multiple methods can
bind to the 18S rRNA. 46,47 It can inhibit osteosarcoma cell further improve the prediction accuracy.
growth by down-regulating the MAPK signaling pathway. HA117, as a lncRNA, is located in the GGL region of
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Li et al. has reported that NME2 was overexpressed in the RGS6 gene. RGS6 contains three structural domains:
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osteosarcoma cell lines, and Western blot analysis showed the RGS region located at the C-terminus, the GGL region,
that the deregulation of NME2 led to the enhancement and the DEP region. The GGL region of RGS6 can bind
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of c-Myc expression, thus promoting the proliferation of to DNA methyltransferase 1-associated protein 1 (DMAP1),
osteosarcoma. In addition, ADAM9 is a target gene of has- which interacts with RGS6 in a DMAP1-dependent manner.
miR-1274a, which may mediate the functional role of has- This interaction between RGS6 and DMAP1 can inhibit
miR-1274a in osteosarcoma progression. It is worth noting DMAP1’s transcriptional inhibitory activity. HA117 may
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that in our analysis, these three reported genes all have a enhance the stem-like characteristics of the HL60/ATRA
negative regulatory relationship with HA117. Therefore, we cell lines in leukemia by inhibiting the ubiquitination and
postulate that down-regulating the expression of HA117 degradation of DNMT1 and down-regulating the expression
through chemotherapy in osteosarcoma may promote the of the GGL domain-containing protein RGS6. In addition,
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up-regulation of these target genes. However, many target Luo et al. found that the expression level of HA117 is
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genes of HA117 have not been reported in relation to negatively associated with DPF3 in Hirschsprung’s disease
osteosarcoma. Therefore, further experiments are needed to colonic segments. These results indicate that HA117 can not
explore their functions. only regulate the expression of adjacent genes, such as RGS6,

In addition, we conducted a Reactome pathway through cis-regulation but can also regulate the expression
analysis on 94 target genes of HA117 to clarify their of distant genes through trans-regulation. In our study,
metabolic pathways. These target genes, mainly associated significant differences in HA117 expression were observed
with chemotherapy, are enriched in the immune system solely between non-chemotherapy and chemotherapy

Volume 3 Issue 3 (2024) 10 doi: 10.36922/td.3670