A concise review of the regulatory, diagnostic, and prognostic implications of HOXB-AS3 in tumors.

Recent studies have reported that HOXB-AS3 (HOXB Cluster Antisense RNA 3) is an intriguing molecule with dual functionality as a long noncoding RNA (lncRNA) and putative coding peptide in tumorigenesis and progression. The significant expression alterations of HOXB-AS3 were detected in diverse cancer types and closely correlated with clinical stage and patient survival. Furthermore, HOXB-AS3 was involved in a spectrum of biological processes in solid tumors and hematological malignancies, such as stemness, lipid metabolism, migration, invasion, and tumor growth. This review comprehensively analyzes its clinical relevance for diagnosis and prognosis across human tumors and summarizes its functional role and regulatory mechanisms in different malignant tumors, including liver cancer, acute myeloid leukemia, ovarian cancer, lung cancer, endometrial carcinoma, colon cancer, and oral squamous cell carcinoma. Overall, HOXB-AS3 emerges as a promising biomarker and novel therapeutic target in multiple human tumors.

Alternative splicing of HOXB-AS3 underlie the promoting effect of nuclear m6A reader YTHDC1 on the self-renewal of leukemic stem cells in acute myeloid leukemia.

This research sought to elucidate the mechanism underlying the self-renewal capacity of leukemic stem cells (LSCs) to offer new insights into the treatment of acute myeloid leukemia (AML). The expression of HOXB-AS3 and YTHDC1 in the AML samples was screened and verified in THP-1 cells and LSCs. The relationship between HOXB-AS3 and YTHDC1 was determined. HOXB-AS3 and YTHDC1 were knocked down through cell transduction to examine the effect of HOXB-AS3 and YTHDC1 on LSCs isolated from THP-1 cells. Tumor formation in mice was used to verify fore experiments. HOXB-AS3 and YTHDC1 were robustly induced in AML, in correlation with adverse prognosis in patients with AML. We found YTHDC1 bound HOXB-AS3 and regulated its expression. Overexpression of YTHDC1 or HOXB-AS3 promoted the proliferation of THP-1 cells and LSCs and impaired their apoptosis, increasing the number of LSCs in the blood and bone marrow of AML mice. YTHDC1 could upregulate the expression of HOXB-AS3 spliceosome NR_033205.1 via the m6A modification of HOXB-AS3 precursor RNA. By this mechanism, YTHDC1 accelerated the self-renewal of LSCs and the subsequent AML progression. This study identifies a crucial role for YTHDC1 in the regulation of LSC self-renewal in AML and suggests a new perspective for AML treatment.

LncRNA HOXB-AS3 binding to PTBP1 protein regulates lipid metabolism by targeting SREBP1 in endometrioid carcinoma.

Endometrial cancer (EC) is a malignant tumor with a high incidence in women, and the survival rate of high-risk patients decreases significantly after disease progression. The regulatory role of long non-coding RNAs (LncRNAs) in tumors has been widely appreciated, but there have been few studies in EC. To investigate the effect of HOXB-AS3 in EC, we used bioinformatics tools for prediction and collected clinical samples to detect the expression of HOXB-AS3. Colony formation assay, MTT assay, flow cytometry and apoptosis assay, and transwell assay were used to verify the role of HOXB-AS3 in EC. HOXB-AS3 was upregulated in EC, promoted the proliferation and invasive ability of EC cells, and inhibited apoptosis. In addition, the ROC curve illustrated its diagnostic value. We explored experiments via lentiviral transduction, FISH, Oil Red O staining, TC and FFA content detection, RNA-pulldown, RIP, and other mechanisms to reveal that HOXB-AS3 can bind to PTBP1 and co-regulate the expression of SREBP1, thereby regulating lipid metabolism in EC cells. To the best of our knowledge, this is the first study on HOXB-AS3 in disorders of lipid metabolism in EC. In addition, we believe HOXB-AS3 has the potential to be a neoplastic marker or a therapeutic target.

Transcriptional suppression of Dicer by HOXB-AS3/EZH2 complex dictates sorafenib resistance and cancer stemness.

Sorafenib is a multikinase inhibitor for the standard treatment of advanced liver cancer patients. However, acquired resistance to sorafenib is responsible for a poor prognosis. Therefore, uncovering the molecular mechanisms underlying sorafenib sensitization can provide biomarkers for sorafenib treatment and improve sorafenib activity in a precise medication. Here, we report that epigenetic suppression of Dicer by the HOXB-AS3/EZH2 complex is responsible for sorafenib resistance. We observed that Dicer expression is inversely correlated with EZH2 levels, HOXB-AS3 expression, sorafenib resistance, and cancer stem cell properties in liver cancer patients. Furthermore, ectopic expression of Dicer induced liver cancer cells resensitization to sorafenib. Mechanistically, we found HOXB-AS3 physically interacts with EZH2 and recruits EZH2 to the Dicer promoter, resulting in epigenetic suppression of Dicer expression. These findings reveal that HOXB-AS3/EZH2 complex-mediated Dicer suppression plays an important role in sorafenib resistance and cancer stemness and provide potential therapeutic strategies for diagnosing and treating liver cancer patients.

A micro-peptide encoded by HOXB-AS3 promotes the proliferation and viability of oral squamous cell carcinoma cell lines by directly binding with IGF2BP2 to stabilize c-Myc.

HOXB-AS3 is a long non-coding RNA and recent studies have shown that the HOXB-AS3-encoded micro-peptide was associated with the progression of colon cancer tumorigenesis; however, the biofunction of HOXB-AS3 varies in different types of cancer and the potential function in oral squamous cell carcinoma (OSCC) is still unknown. The Cancer Genome Atlas (TCGA) database was searched and the expression patterns of HOXB-AS3 in head and neck carcinoma were analyzed. Reverse transcription-quantitative PCR and western blot analysis was used to measure the mRNA and protein expression level of HOXB-AS3 in patients with OSCC, respectively. Next, HOXB-AS3 was knocked down in 2 OSCC cell lines to investigate the biological function of the HOXB-AS3-encoded protein using a Cell Counting Kit-8 and colony formation assays. To further identify the potential mechanism of the HOXB-AS3-encoded protein, co-immunoprecipitation was also used to detect the interaction between HOXB-AS3 and IGF2BP2, while HOXB-AS3 was re-expressed to determine whether the HOXB-AS3-encoded protein and not HOXB-AS3 exerted its function in OSCC. HOXB-AS3 was upregulated in OSCC tissues, in both TCGA database and in patients with OSCC recruited into the present study. HOXB-AS3 was associated with poor prognosis in OSCC. The proliferation and viability decreased in the 2 OSCC cell lines following knock down of HOXB-AS3. HOXB-AS3 was also found to encode a protein that directly interacted with IGF2BP2 and thereby promoted the stability of c-myc. Taken together, the results from the present study indicated that increased HOXB-AS3 expression was associated with poor prognosis in OSCC. This indicated that HOXB-AS3 and its encoded protein promoted OSCC cell proliferation and viability by maintaining c-Myc mRNA stability by directly binding to IGF2BP2.

LncRNA HOXB-AS3 promotes growth, invasion and migration of epithelial ovarian cancer by altering glycolysis.

HEADING AIMS: LncRNA HOXB-AS3 is proved as an oncogene in tumors. Herein, we determine the function and mechanism of HOXB-AS3 in epithelial ovarian cancer (EOC) cells. MATERIALS AND METHODS: Chi-square test, Kaplan-Meier (KM) analysis and Cox regression analysis were used to analyze the clinicopathological features of HOXB-AS3 in EOC patients. CCK8, transwell and wound healing assay were used to test the function of HOXB-AS3. Luciferase reporter assay, western blot and glycolysis rate assay were used for further mechanistic studies. KEY FINDINGS: HOXB-AS3 was abundantly expressed in EOC tissues, and higher levels of HOXB-AS3 in EOC patients were significantly associated with disease status and overall survival status. EOC patients with high levels of HOXB-AS3 had strikingly shorter disease-free survival (DFS) and overall survival (OS) times than those with low levels. HOXB-AS3 also might as an independent prognostic factor. Further study revealed knockdown of HOXB-AS3 significantly inhibited the proliferation, invasion and migration of EOC cells. Mechanistic investigations suggested that knockdown of HOXB-AS3 could decrease lactate dehydrogenase A (LDHA) expression and the extracellular acidification rate (ECAR) by sponging miR-378a-3p. SIGNIFICANCE: To our knowledge, this is the first study to suggest that HOXB-AS3 could crosstalk with miRNA in the cytoplasm and alter glycolysis in cancer cells. Our results improve our understanding of the mechanism of HOXB-AS3 and suggest that HOXB-AS3 can act as a predictor of OS and a target for EOC therapies.

lncRNA HOXB-AS3 exacerbates proliferation, migration, and invasion of lung cancer via activating the PI3K-AKT pathway.

Lung cancer remains the leading cause of cancer-related death all over the world. In spite of the great advances made in surgery and chemotherapy, the prognosis of lung cancer patients is poor. A substantial fraction of long noncoding RNAs (lncRNAs) can regulate various cancers. A recent study has reported that lncRNA HOXB-AS3 plays a critical role in cancers. However, its biological function remains unclear in lung cancer progression. In the current research, we found HOXB-AS3 was obviously elevated in NSCLC tissues and cells. Functional assays showed that inhibition of HOXB-AS3 was able to repress A549 and H1975 cell proliferation, cell colony formation ability and meanwhile, triggered cell apoptosis. Furthermore, the lung cancer cell cycle was mostly blocked in the G1 phase whereas the cell ratio in the S phase was reduced. Also, A549 and H1975 cell migration and invasion capacity were significantly repressed by the loss of HOXB-AS3. The PI3K/AKT pathway has been implicated in the carcinogenesis of multiple cancers. Here, we displayed that inhibition of HOXB-AS3 suppressed lung cancer cell progression via inactivating the PI3K/AKT pathway. Subsequently, in vivo experiments were utilized in our study and it was demonstrated that HOXB-AS3 contributed to lung cancer tumor growth via modulating the PI3K/AKT pathway. Overall, we implied that HOXB-AS3 might provide a new perspective for lung cancer treatment via targeting PI3K/AKT.

lncRNA HOXB-AS3 protects doxorubicin-induced cardiotoxicity by targeting miRNA-875-3p.

Protective role of lncRNA HOXB-AS3 in doxorubicin (DOX)-induced cardiotoxicity and its mechanism were studied. Viability of PC and H9c2 cells treated with different doses of DOX was determined through CCK-8 assay. Relative level of HOXB-AS3 in DOX-treated cardiomyocytes was detected. Regulatory effect of HOXB-AS3 on the proliferative ability of DOX-treated cardiomyocytes was assessed. Through dual-luciferase reporter gene assay, the binding relationship between HOXB-AS3 and miRNA-875-3p was verified. Rescue experiments were conducted to explore the role of HOXB-AS3/miRNA-875-3p in influencing the proliferation of DOX-treated cardiomyocytes. The proliferative ability of cardiomyocytes was dose-dependently downregulated after DOX treatment. Relative level of HOXB-AS3 was upregulated in DOX-treated cardiomyocytes. Silence of HOXB-AS3 in cardiomyocytes undergoing DOX treatment markedly elevated their proliferative ability. miRNA-875-3p was the direct target of HOXB-AS3. Knockdown of miRNA-875-3p reversed the role of HOXB-AS3 in regulating the proliferative ability of cardiomyocytes. HOXB-AS3 protects DOX-induced suppression in the proliferation of cardiomyocytes through targeting and downregulating miRNA-875-3p.

Overexpression of long noncoding RNA HOXB-AS3 indicates an unfavorable prognosis and promotes tumorigenesis in epithelial ovarian cancer via Wnt/ß-catenin signaling pathway.

Long noncoding RNA HOXB cluster antisense RNA 3 (HOXB-AS3) has been reported to be dysregulated in several tumors. The present study mainly aims at the investigation in how HOXB-AS3 works in epithelial ovarian cancer (EOC) and to elucidate the mechanism involved. Initially, 'GEPIA' was mined to examine the differential expression levels and prognostic value of HOXB-AS3 in EOC patients. The expression of HOXB-AS3 in EOC cell lines and patient specimens was examined with quantitative RT-PCR. Simultaneously, the correlation of HOXB-AS3 expression with a variety of clinicopathological factors and patient survival was analyzed. MTT, colony formation and flow cytometry assays were performed to analyze the cell viability of EOC cells. Wound healing and Transwell assays were carried out to determine EOC cells' capability of migrating and invading. The impact of HOXB-AS3 on EMT and Wnt/ß-catenin signaling was explored with the approach of Western blot. We found that in both EOC cell lines and tissues, HOXB-AS3 expression was significantly up-regulated, and its high expression was an independent prognostic marker of poor outcome for EOC patients. In vitro loss-of-function assays revealed that HOXB-AS3 knockdown inhibited EOC cells proliferation, migration, invasion and EMT, and induced EOC cells' apoptosis. Furthermore, we validated that down-regulated HOXB-AS3 attenuated the activity of Wnt/ß-catenin signaling to suppress the invasion, migration and proliferation of EOC cells. To sum up, the present study came up with the conclusion that HOXB-AS3 acts as an oncogenic gene in EOC progression through HOXB-AS3-Wnt/ß-catenin signaling regulation, providing a novel insight into EOC tumorigenesis.

Long non-coding RNA HOXB-AS3 promotes myeloid cell proliferation and its higher expression is an adverse prognostic marker in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. METHODS: shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. RESULTS: Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P <  0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group. CONCLUSIONS: This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.