The strict regulation of HIF-1α by non-coding RNAs: new insight towards proliferation, metastasis, and therapeutic resistance strategies

Jawad, Sabrean Farhan; Altalbawy, Farag M. A.; Hussein, Radhwan M.; Fadhil, Ali Abdulhussain; Jawad, Mohammed Abed; Zabibah, Rahman S.; Taraki, Tasneem Younus; Mohan, Chakrabhavi Dhananjaya; Rangappa, Kanchugarakoppal S.

doi:10.1007/s10555-023-10129-8

Cited by 7 publications

(5 citation statements)

References 207 publications

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“…This is because rapidly growing malignant tumors disrupt the balance between oxygen consumption and supply, leading to a hypoxic environment inside cancer cells. The hypoxic environment of cancer cells activates a series of cascading factors, and the interaction of these factors contributes to issues such as cancer metastasis, invasion, resistance changes, and poor prognosis [28][29][30][31]. Therefore, we examined the changes in DKK2 under simulated in vivo hypoxic conditions and confirmed that the expression of DKK2 increases under hypoxic conditions.…”

Section: Discussionmentioning

confidence: 95%

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

Guo,

Qu,

et al. 2024

Aging

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Objective: This study aimed to investigate the impact of Dickkopf 2 (DKK2) on the progression of oral squamous cell carcinoma (OSCC) and explore its role in the PI3K/AKT signaling transduction pathway. Materials and Methods: The study initially examined the expression of the DKK2 gene in OSCC tissues and normal tissues. Simultaneously, the expression of DKK2 in HOK cells and OSCC cells was verified, and changes in DKK2 expression under hypoxic conditions were detected. DKK2 overexpression and knockdown were performed in SCC-15 and CAL-27 cells. Subsequently, the effects of DKK2 on the proliferation, migration and invasion of OSCC were detected. Western blotting was employed to detect the expression of key proteins in the DKK2/PI3K/AKT signaling axis before and after transfection, and further explore the relevant molecular mechanisms. Results: Compared to normal tissues, DKK2 expression was elevated in OSCC tissues. The expression of DKK2 in the SCC-15 and CAL-27 cell lines was higher than that in HOK cells, and hypoxic conditions could promote DKK2 expression. DKK2 overexpression promoted cell proliferation, migration, and invasion, while DKK2 knockdown inhibited these processes. DKK2 overexpression activated the PI3K/AKT pathway, while DKK2 knockdown suppressed this pathway. Conclusion: This study suggests that hypoxic conditions enhance the expression of DKK2 in OSCC. DKK2 regulates the proliferation, migration, and invasion of OSCC through the PI3K/AKT signaling pathway.

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Section: Discussionmentioning

confidence: 95%

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

Guo,

Qu,

et al. 2024

Aging

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“…A recent study reported HIF-1α as a critical transcription factor of HB-EGF in hepatocellular carcinoma ( 25 ). HIF-1α is a regulator of homeostasis response to cellular hypoxia ( 26 ), which was also involved in the development of many malignancies and highly correlated with tumor metastasis, prognosis, chemotherapy drug resistance, and other factors ( 27 - 29 ). Our data showed that HIF-1α amounts were decreased with decreasing B7-H3 levels.…”

Section: Resultsmentioning

confidence: 99%

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α

Hu,

Wang,

Wang

et al. 2024

J Gastrointest Oncol

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Background B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

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“…Radiogenomic analysis revealed that molecular pathways characterizing tumor invasion and metastasis, such as EMT, angiogenesis, and hypoxia, were enriched in the high-DPS subtype. EMT and angiogenesis are key morphogenetic processes in cancer progression [42], and EMT can be driven by hypoxia [43], a condition associated with various biological processes such as cell proliferation, EMT, angiogenesis, therapy resistance, and metastasis [44]. Proteomic analysis indicated elevated expression of proteins such as EGFR and HER2 in the high-DPS subtype, while proteins such as ERK2 exhibited higher expression in the low-DPS subtype.…”

Section: Discussionmentioning

confidence: 99%

Biologically interpretable multi-task deep learning pipeline predicts molecular alterations, grade, and prognosis in glioma patients

Zhang,

Wu,

Zhang

et al. 2024

Preprint

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Deep learning models have been developed for various predictions in glioma; yet, they were constrained by manual segmentation, task-specific design, or a lack of biological interpretation. Herein, we aimed to develop an end-to-end multi-task deep learning (MDL) pipeline that can simultaneously predict molecular alterations and histological grade (auxiliary tasks), as well as prognosis (primary task) in gliomas. Further, we aimed to provide the biological mechanisms underlying the model's predictions. We collected multiscale data including baseline MRI images from 2,776 glioma patients across two private (FAHZU and HPPH, n=1,931) and three public datasets (TCGA, n=213; UCSF, n=410; and EGD, n=222). We trained and internally validated the MDL model using our private datasets, and externally validated it using the three public datasets. We used the model-predicted deep prognosis score (DPS) to stratify patients into low-DPS and high-DPS subtypes. Additionally, a radio-multiomics analysis was conducted to elucidate the biological basis of the DPS. In the external validation cohorts, the MDL model achieved average areas under the curve of 0.892-0.903, 0.710-0.894, and 0.850-0.879 for predicting IDH mutation status, 1p/19q co-deletion status, and tumor grade, respectively. Moreover, the MDL model yielded a C-index of 0.723 in the TCGA and 0.671 in the UCSF for the prediction of overall survival. The DPS exhibits significant correlations with activated oncogenic pathways, immune infiltration patterns, specific protein expression, DNA methylation, tumor mutation burden, and tumor-stroma ratio. Accordingly, our work presents an accurate and biologically meaningful tool for predicting molecular subtypes, tumor grade, and survival outcomes in gliomas, which provides personalized clinical decision-making in a global and non-invasive manner.

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The strict regulation of HIF-1α by non-coding RNAs: new insight towards proliferation, metastasis, and therapeutic resistance strategies

Cited by 7 publications

References 207 publications

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

DKK2 promotes the progression of oral squamous cell carcinoma through the PI3K/AKT signaling pathway

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α

Biologically interpretable multi-task deep learning pipeline predicts molecular alterations, grade, and prognosis in glioma patients

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