<i>Noxa</i> upregulation and 5‐gene apoptotic biomarker panel in colorectal cancer

Kosmidou, Vivian; Vlassi, Margarita; Anagiotos, Kyriakos; Raftopoulou, Sofia; Kalogerakou, Eirini; Skarmalioraki, Salomi; Aggeli, Chrysanthi; Choreftaki, Theodosia; Zografos, George; Pintzas, Alexander

doi:10.1111/eci.13353

Cited by 6 publications

(4 citation statements)

References 37 publications

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“…Targeting ALOX5 promotes colorectal cancer cell proliferation, and silencing of ALOX5 inhibited colorectal cancer cell growth [ 28 , 29 ]. PMAIP1 is involved in the intrinsic apoptosis pathway, selectively binds to MCL1, and prevents MCL1 to inhibiting apoptosis in colorectal cancer [ 30 ]. EGR1 high expression correlates with resistance to anti-EGFR treatment in metastatic colorectal cancer patients treated with cetuximab, and silencing EGR1 expression promotes killing HCT116 colorectal cancer cells and delaying tumor growth [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

Líu

Zhang

Zhen

et al. 2021

Journal of Immunology Research

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Background. Preoperative chemoradiotherapy (pCRT) is a common and essential therapeutic strategy for patients with locally advanced rectal cancer (LARC), but poor tumor response and therapeutic resistance to chemoradiotherapy have appeared usually among persons and affected those patients’ survival prognosis. The resistance to chemoradiotherapy in rectal cancer is difficult to predict. This study was aimed at evaluating the role of V-set and transmembrane domain containing 2 like protein (VSTM2L) in resistance to chemoradiotherapy in rectal cancer. Methods. Analysis of the GEO profiling datasets of rectal cancer patients receiving pCRT disclosed that VSTM2L as a candidate gene was significantly upregulated in nonresponders of rectal cancer with pCRT. The mRNA and protein expression of VSTM2L was detected by quantitate real-time PCR, western blotting, and immunohistochemistry in six rectal cancer biopsy tissues before pCRT. Furthermore, the rectal cancer patient-derived organoids were cultured to evaluate the association of VSTM2L expression and tumor response to CRT. Overexpression of VSTM2L in cancer cells treated with CRT was analyzed for the function of cell proliferation and viability, clone formation, DNA damage repair, and apoptosis ability. The GSEA and RNA-sequence analysis were used to find the downstream mechanism of VSTM2L overexpression in cells treated with CRT. Results. The mRNA levels of VSTM2L were significantly downregulated in normal rectal tissues compared to tumor tissues and were upregulated in nonresponders of rectal cancer patients receiving pCRT and positively correlated with poor survival prognosis from GEO datasets. High expression of VSTM2L was significantly associated with tumor regression after pCRT ( P = 0.030 ). Moreover, high expression of VSTM2L reduced γ-H2AX expression in rectal cancer patient-derived organoids treated with CRT. The overexpression of VSTM2L in colorectal cancer cells induced resistance to CRT via promoting cell proliferation and inhibiting apoptosis. The molecular mechanism revealed that the overexpression of VSTM2L induced resistance to CRT through downstream IL-4 signaling affecting the progress of cell proliferation and apoptosis. Conclusion. The high expression of VSTM2L induced resistance to CRT, and adverse survival outcomes served as a prognostic factor in patients with rectal cancer receiving pCRT, suggesting that VSTM2L high expression may be a potential resistant predictable biomarker for LARC patients receiving pCRT.

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Section: Discussionmentioning

confidence: 99%

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

Líu

Zhang

Zhen

et al. 2021

Journal of Immunology Research

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“…The inherent challenges of delayed diagnosis and the high propensity for metastasis in gastric cancer contribute to elevated mortality rates, with a median survival rate of less than 1 year for patients with metastatic gastric cancer 37 . Cancer cells exhibit marked genetic and epigenetic alterations, frequently instigating the initiation and progression of malignancies by perturbing the molecular and cellular processes governing cancer cells 38 . Consequently, a comprehensive exploration of the molecular and cellular mechanisms underpinning the pathogenesis of gastric cancer is imperative for precise diagnosis, prognostic assessment, and therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Noxa inhibits oncogenesis through ZNF519 in gastric cancer and is suppressed by hsa-miR-200b-3p

Shi,

Ding,

Dai

et al. 2024

Sci Rep

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While Phorbol-12-myristate-13-acetate-induced protein 1 (Noxa/PMAIP1) assumes a pivotal role in numerous tumors, its clinical implications and underlying mechanisms of gastric cancer (GC) are yet enigmatic. In this investigation, our primary objective was to scrutinize the clinical relevance and potential mechanisms of Noxa in gastric cancer. Immunohistochemical analysis was conducted on tissue microarrays comprising samples from a meticulously characterized cohort of 84 gastric cancer patients, accompanied by follow-up data, to assess the expression of Noxa. Additionally, Noxa expression levels in gastric cancer clinical samples and cell lines were measured through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. The effect of Noxa expression on the prognosis of patients with gastric cancer was evaluated using Kaplan–Meier survival. Further insight into the role of Noxa in driving gastric cancer progression was gained through an array of experimental techniques, including cell viability assays (CCK8), plate cloning assays, transwell assays, scratch assays, and real-time cell analysis (RTCA). Potential upstream microRNAs (miRNAs) that might modulate Noxa were identified through rigorous bioinformatics analysis, substantiated by luciferase reporter assays and Western blot experiments. Additionally, we utilized RNA sequencing, qRT-PCR, and Western blot to identify proteins binding to Noxa and potential downstream target. Finally, we utilized BALB/c nude mice to explore the role of Noxa in vivo. Our investigation unveiled a marked downregulation of Noxa expression in gastric cancer and underscored its significance as a pivotal prognostic factor influencing overall survival (OS). Noxa overexpression exerted a substantial inhibitory effect on the proliferation, migration and invasion of GC cells. Bioinformatic analysis and dual luciferase reporter assays unveiled the capacity of hsa-miR-200b-3p to interact with the 3′-UTR of Noxa mRNA, thereby orchestrating a downregulation of Noxa expression in vitro, consequently promoting tumor progression in GC. Our transcriptome analysis, coupled with mechanistic validation, elucidated a role for Noxa in modulating the expression of ZNF519 in the Mitophagy-animal pathway. The depletion of ZNF519 effectively reversed the oncogenic attributes induced by Noxa. Upregulation of Noxa expression suppressed the tumorigenesis of GC in vivo. The current investigation sheds light on the pivotal role of the hsa-miR-200b-3p/Noxa/ZNF519 axis in elucidating the pathogenesis of gastric cancer, offering a promising avenue for targeted therapeutic interventions in the management of this challenging malignancy.

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“…These findings are commensurate with our hypothesis that functional NOXA is important in the execution of successful apoptosis in response to therapy, and that a decline in NOXA expression following therapy is likely to be associated with suboptimal responses to chemotherapy 15 , 28 . In other cancers, Kosmidou et al reported that NOXA mRNA was overexpressed in 66% of the examined colorectal cancer tumor samples relative to their paired non-malignant colonic tissue counterparts 45 . However, the authors performed IHC staining for NOXA protein in 39 samples that “showed high levels of differential mRNA expression” 45 , but found negative NOXA expression in some cases and did not report detailed findings on the IHC staining, suggesting that the IHC approach might be a better assay than mRNA expression for NOXA detection.…”

Section: Discussionmentioning

confidence: 99%

“…In other cancers, Kosmidou et al reported that NOXA mRNA was overexpressed in 66% of the examined colorectal cancer tumor samples relative to their paired non-malignant colonic tissue counterparts 45 . However, the authors performed IHC staining for NOXA protein in 39 samples that “showed high levels of differential mRNA expression” 45 , but found negative NOXA expression in some cases and did not report detailed findings on the IHC staining, suggesting that the IHC approach might be a better assay than mRNA expression for NOXA detection. Unfortunately, further evidence on the evaluation of NOXA protein expression levels in clinical cancer samples is parsimonious.…”

Section: Discussionmentioning

confidence: 99%

NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy

Al Shboul,

El-Sadoni,

Alhesa

et al. 2023

Sci Rep

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Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1, the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC). PAMIP1 expression significantly declined in post-NAC in the two sets, and in our cohort, 75% of the samples exhibited a downregulation in NOXA post-NAC. Matched samples that showed a decline in NOXA post-NAC were examined for TIS based on a signature of downregulated expression of Lamin-B1 and Ki-67 and increased p16INK4a, and the majority exhibited a decrease in Lamin B1 (66%) and Ki-67 (80%), and increased p16INK4a (49%). Since our cohort consisted of patients that did not develop complete pathological response, such findings have clinical implications on the role of TIS and NOXA downregulation in mediating suboptimal responses to the currently established NAC.

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Noxa upregulation and 5‐gene apoptotic biomarker panel in colorectal cancer

Cited by 6 publications

References 37 publications

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

Noxa inhibits oncogenesis through ZNF519 in gastric cancer and is suppressed by hsa-miR-200b-3p

NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy

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