Overexpression of Hypoxia-Inducible Factor-1α and Its Relation with Aggressiveness and Grade of Oral Squamous Cell Carcinoma

Sumera, Sumera; Ali, Asif; Yousafzai, Yasar Mehmood; Durrani, Zubair; Alorini, Mohammed; Aleem, Benish; Zahir, Rabia

doi:10.3390/diagnostics13030451

Cited by 8 publications

(5 citation statements)

References 24 publications

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“…HIF-1α is a tumor angiogenic transcription factor [ 25 ]. Evidence suggests that HIF-1α expression is linked to tumor promotion in human OSCC [ 26 ] and correlates with the growth of human OSCC cells [ 27 ]. Previously, we have shown that the HIF-1α protein is highly expressed in HSC-3 cells under a normoxic condition [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

PHA-665752’s Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells

Yadav,

Wang,

Shin

et al. 2024

IJMS

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c-Met is a tyrosine-kinase receptor, and its aberrant activation plays critical roles in tumorigenesis, invasion, and metastatic spread in many human tumors. PHA-665752 (PHA) is an inhibitor of c-Met and has antitumor effects on many hematological malignancies and solid cancers. However, the activation and expression of c-Met and its role and the antitumor effect of PHA on human oral squamous cell carcinoma (OSCC) cells remain unclear. Here, we investigated the activation and expression of c-Met and the effects of PHA on the growth of a highly tumorigenic HSC-3 human OSCC cell line with high c-Met phosphorylation and expression. Of note, c-Met was highly expressed and phosphorylated on Y1234/1235 in HSC-3 cells, and PHA treatment significantly suppressed the growth and induced apoptosis of these cells. Moreover, PHA that inhibited the phosphorylation (activation) of c-Met further caused the reduced phosphorylation and expression levels of Src, protein kinase B (PKB), mammalian target of rapamycin (mTtor), and myeloid cell leukemia-1 (Mcl-1) in HSC-3 cells. In addition, the antiangiogenic property of PHA in HSC-3 cells was shown, as evidenced by the drug’s suppressive effect on the expression of hypoxia-inducible factor-1α (HIF-1α), a critical tumor angiogenic transcription factor. Importantly, genetic ablation of c-Met caused the reduced growth of HSC-3 cells and decreased Src phosphorylation and HIF-1α expression. Together, these results demonstrate that c-Met is highly activated in HSC-3 human oral cancer cells, and PHA exhibits strong antigrowth, proapoptotic, and antiangiogenic effects on these cells, which are mediated through regulation of the phosphorylation and expression of multiple targets, including c-Met, Src, PKB, mTOR, Mcl-1, and HIF-1α.

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Section: Resultsmentioning

confidence: 99%

PHA-665752’s Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells

Yadav,

Wang,

Shin

et al. 2024

IJMS

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“…HIF1α, a key transcription factor in cellular responses to hypoxia, has been implicated in cancer [ 21 ]. HIF1α is often overexpressed in cancer tissues and associated with patients’ poor clinical prognosis [ 22 – 25 ]. HIF1α promotes tumor progression by regulating the transcription of various genes involved in metabolic reprogramming, metastasis, chemotherapy resistance, and immunosuppression [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Shi,

Fang,

et al. 2024

Oncogenesis

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Accumulating studies have shown that E3 ligases play crucial roles in regulating cellular biological processes and signaling pathways during carcinogenesis via ubiquitination. Tripartite-motif (TRIM) ubiquitin E3 ligases consist of over 70 members. However, the clinical significance and their contributions to tumorigenesis remain largely unknown. In this study, we analyzed the RNA-sequencing expression of TRIM E3 ligases in colorectal cancer (CRC) and identified 10 differentially expressed genes, among which TRIM1 expression predicted poor prognosis of CRC patients. We demonstrated that TRIM1 expression is positively associated with CRC pathological stages, and higher expression is positively correlated with infiltrating levels of immune cells and immunotherapy biomarkers. TRIM1 expression promotes the proliferation and migration of colorectal cancer cells in vitro and in vivo. Transcriptional analysis showed that TRIM1 is responsible for metabolism promotion and immune suppression. Mechanistically, we found that TRIM1 binds HIF1α and mediates its K63-linked ubiquitination, which is required for HIF1α nuclear translocation and subsequent activation. Ubiquitination occurs at Lys214 in the loop between the two PAS domains of HIF1α, and mutation of Lys214 severely disturbs the function of HIF1α. Besides, HIF1α ubiquitination enhances its binding with proteins involved in cellular trafficking and nucleocytoplasmic transport pathway. Collectively, our results indicate TRIM1’s role in predicting prognosis and reveal how TRIM1 functions to upregulate HIF1α expression and promote tumor cell proliferation.

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“…Regarding tumor size, previous studies showed a correlation between HIF-1α expression and renal tumor size, particularly in clear cell renal cell carcinoma (ccRCC) ( 21 ). Studies have shown that HIF-1α expression tends to be higher in larger tumors since HIF-1α plays a crucial role in the regulation of cellular responses to hypoxia (low oxygen levels) ( 22 ). As the tumor grows, it may outgrow its blood supply, leading to areas of hypoxia within the tumor mass.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of HIF1A and its downstream target VEGFA in the main subtypes of renal cell carcinoma and their impact on patient survival

Strikic,

Kokeza,

Ogorevc

et al. 2023

Front. Oncol.

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Renal cell carcinoma (RCC) represents around 3% of all cancers, with the most frequent histological types being clear-cell RCC (ccRCC), followed by papillary (pRCC) and chromophobe (chRCC). Hypoxia-inducible factors (HIFs), which promote the expression of various target genes, including vascular endothelial growth factor (VEGF) and the high- affinity glucose transporter 1, have an important role in the pathogenesis of RCC. This study investigated the immunohistochemical expression of HIF-1α and VEGF-A, showing significantly higher HIF-1α nuclear expression in pRCC compared to ccRCC, while there was no significant difference in VEGF-A protein expression between the analyzed histological RCC subtypes. The quantitative reverse transcription polymerase chain reaction for HIF1A showed no statistical difference between histological types. Data from publicly available RNA sequencing databases were analyzed and showed that, compared to healthy kidney tissue, VEGFA was significantly up-regulated in ccRCC and significantly down-regulated in pRCC. The comparison between histological subtypes of RCC revealed that VEGFA was significantly up-regulated in ccRCC compared to both pRCC and chRCC. There was no statistically significant difference in survival time between HIF1A high- and low-expression groups of patients. As for VEGFA expression, pRCC patients with low expression had a significantly higher survival rate compared to patients with high VEGFA expression.

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Overexpression of Hypoxia-Inducible Factor-1α and Its Relation with Aggressiveness and Grade of Oral Squamous Cell Carcinoma

Cited by 8 publications

References 24 publications

PHA-665752’s Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells

PHA-665752’s Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells

An E3 ligase TRIM1 promotes colorectal cancer progression via K63-linked ubiquitination and activation of HIF1α

Differential expression of HIF1A and its downstream target VEGFA in the main subtypes of renal cell carcinoma and their impact on patient survival

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