Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

Huang, Wei-Chao; Jeng, Yung‐Ming; Lai, Hung-Wen; Fong, I‐Kong; Sheu, Fang-Yu Bonnie; Lai, Po-Lin; Yuan, Ray-Hwang

doi:10.1371/journal.pone.0119181

Cited by 36 publications

(47 citation statements)

References 46 publications

(60 reference statements)

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“…As for the P21, it displayed over expression in 83.8% of bladder cancer cases which agrees with several studies [28][29][30]. P21 overexpression reflected poor prognostic impact in BC which is proved by its role in tumorgenesis and cancer progression [29][30][31][32][33].…”

Section: Discussionsupporting

confidence: 87%

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ROC-1, P21 and CAIX as markers of tumor aggressiveness in bladder carcinoma in Egyptian patients

et al. 2020

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Background: Bladder cancer (BC) is one of the most common malignancies in Egypt, representing about 8.7% of cancers in both sexes with more predominance in males, making identification of valuable predictive and prognostic markers, mandatory. Cullin-RING ligases (CRL) play an important role in the ubiquitination of cell cycle-related proteins or other proteins (e.g., DNA replication protein, signal transduction protein). Regulator of Cullins-1 (ROC-1) is a key subunit of CRL. P21 belongs to the family of cyclin dependent kinase inhibitors (CKIs) which regulates cell cycle by inactivating Cyclin-Dependent Kinases key regulators of the cell cycle. CAIX a highly active member of the family of carbonic anhydrases has gained much interest as a hypoxic marker. Hypoxia is a consequence of the rapid growth of many tumors, including bladder cancer, and is an important regulator of gene expression and resistance to chemotherapy and radiotherapy. Therefore the purpose of this study is to evaluate the role of ROC-1, CAIX and P21 and its relationship with the clinico-pathological features of bladder cancer in Egyptian patients. Methods: Using the standard immunohistochemical technique, ROC-1, CAIX and P21 expression in 80 primary bladder carcinomas and 15 normal bladder specimens as control group were assessed. The bladder carcinoma cases included 50 cases with muscle invasive bladder cancer and 30 cases with non-muscle invasive bladder cancer. Results: Over expression of ROC-1, CAIX and P21 in BC were significantly associated with muscularis propria invasion and high grade BC. ROC-1, CAIX and P21, showed significant inverse relationship in primary BC cases. CAIX expression was significantly higher in BC compared with controls. Regarding the survival analysis, expression of ROC-1, CAIX and P21 didn't affect the survival of BC patients. Conclusions: High expression of ROC-1, CAIX and P21 could be promising potential biomarkers for identifying patients with poor prognostic factors in bladder cancer serving as potential targets for cancer therapy.

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Section: Discussionsupporting

confidence: 87%

“…It has been proposed that progressive cancers accumulate p21 resulting in proliferation of the tumor cells. Also, in BC p21 can act in p53 dependent manner which is one of the predominant components of BC development or by other p53independent pathways, including transforming growth factor beta (TGF-β) signaling [30].…”

Section: Discussionmentioning

confidence: 99%

ROC-1, P21 and CAIX as markers of tumor aggressiveness in bladder carcinoma in Egyptian patients

et al. 2020

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“…CAIX has been a major target in cancer therapeutics (McDonald et al , 2012). This is due to the fact that CAIX overexpression is predominantly associated with poor prognosis, particularly in hypoxic tumours (Driessen et al , 2006; Huang et al , 2015). CAIX, a carbonic anhydrase, is an important regulator of cellular pH during hypoxia (Dubois et al , 2011; Swietach et al , 2007).…”

Section: Discussionmentioning

confidence: 99%

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

Abd‐Aziz

Stanbridge

Shafee

2016

Journal of General Virology

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Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.

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“…However, HIF‐1‐dependent carbonic anhydrases were repeatedly demonstrated to be abnormally overexpressed in cancer cells. While conventional renal cell cancer and several epithelial cancer types (gastric and lung adenocarcinomas) showed intrinsic CAIX positivity, many other neoplastic tissues and especially non‐epithelial cancers (including glioblastoma) expressed CAIX and/or CAXII in a hypoxia‐dependent fashion . Based on several studies, a strong prognostic significance of CAIX in different types of cancer (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…While conventional renal cell cancer and several epithelial cancer types (gastric and lung adenocarcinomas) showed intrinsic CAIX positivity, many other neoplastic tissues and especially non-epithelial cancers (including glioblastoma) expressed CAIX and/or CAXII in a hypoxia-dependent fashion. [15][16][17] Based on several studies, a strong prognostic significance of CAIX in different types of cancer (e.g. breast, head and neck, stomach, liver, pancreas, colorectal carcinomas) was suggested.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma

et al. 2019

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Aims The present study evaluates the impact of hypoxia‐related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma (cHL). Methods and results Eighty‐one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia‐related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin–Reed–Sternberg (HRS) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX+ positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX/Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX+ positive compared to CAIX− negative HRS cells (P < 0.001). Seventy‐two months’ progression‐free survival (PFS) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) (P < 0.001), while the overall survival (OS) did not differ (P = 0.097). Conclusion Hypoxic stress‐related adaptation – highlighted by CAIX expression – results in cellular quiescence in HRS cells, potentially contributing to the short‐term failure of the standard chemotherapy in cHL.

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Expression of Hypoxic Marker Carbonic Anhydrase IX Predicts Poor Prognosis in Resectable Hepatocellular Carcinoma

Cited by 36 publications

References 46 publications

ROC-1, P21 and CAIX as markers of tumor aggressiveness in bladder carcinoma in Egyptian patients

ROC-1, P21 and CAIX as markers of tumor aggressiveness in bladder carcinoma in Egyptian patients

Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53

Hypoxia‐related carbonic anhydrase IX expression is associated with unfavourable response to first‐line therapy in classical Hodgkin's lymphoma

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