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Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

Lian YF, Yuan J, Cui Q, Feng QS, Xu M, Bei JX, Zeng YX, Feng L - PLoS ONE (2016)

Bottom Line: Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining.In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis.Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

ABSTRACT
Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

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Elevated KLHDC4 expression correlates with poor prognosis in NPC patients.(A) Criteria for scoring of KLHDC4 expression intensity. Representative images are shown. All images were obtained and processed under identical conditions. Scale bars: 100 μm. (B-C) Kaplan-Meier analysis of KLHDC4 expression and overall survival (B) and metastasis-free survival rate (C) of NPC patients.
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pone.0152820.g002: Elevated KLHDC4 expression correlates with poor prognosis in NPC patients.(A) Criteria for scoring of KLHDC4 expression intensity. Representative images are shown. All images were obtained and processed under identical conditions. Scale bars: 100 μm. (B-C) Kaplan-Meier analysis of KLHDC4 expression and overall survival (B) and metastasis-free survival rate (C) of NPC patients.

Mentions: To investigate whether KLHDC4 expression can serve as a novel prognostic marker for NPC patients, we examined the correlation of KLHDC4 expression with clinicopathological factors including age, sex and pathological stage in 168 NPC patients. The staining intensity and distribution varied among the samples (Fig 2A), and a cutoff value according to the ROC curve was used to separate patients into two groups: a low KLHDC4 group (score ≤4.5, N = 103) and a high KLHDC4 group (score >4.5, N = 65). As shown in Table 2, KLHDC4 expression was significantly correlated with T classification (P = 0.016), N classification (P = 0.043) and total staging (P = 0.002). No difference was noted in KLHDC4 expression when stratified by gender (P = 1.000), age (P = 0.754), or M stage (P = 0.300). The Kaplan-Meier survival curves showed that the patients with high KLHDC4 expression had a significantly poorer overall survival (OS) and metastasis-free survival (MFS) when compared with patients with low KLHDC4 expression, as defined by the log-rank test (P = 0.005, Fig 2B; P = 0.012, Fig 2C).


Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.

Lian YF, Yuan J, Cui Q, Feng QS, Xu M, Bei JX, Zeng YX, Feng L - PLoS ONE (2016)

Elevated KLHDC4 expression correlates with poor prognosis in NPC patients.(A) Criteria for scoring of KLHDC4 expression intensity. Representative images are shown. All images were obtained and processed under identical conditions. Scale bars: 100 μm. (B-C) Kaplan-Meier analysis of KLHDC4 expression and overall survival (B) and metastasis-free survival rate (C) of NPC patients.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4816273&req=5

pone.0152820.g002: Elevated KLHDC4 expression correlates with poor prognosis in NPC patients.(A) Criteria for scoring of KLHDC4 expression intensity. Representative images are shown. All images were obtained and processed under identical conditions. Scale bars: 100 μm. (B-C) Kaplan-Meier analysis of KLHDC4 expression and overall survival (B) and metastasis-free survival rate (C) of NPC patients.
Mentions: To investigate whether KLHDC4 expression can serve as a novel prognostic marker for NPC patients, we examined the correlation of KLHDC4 expression with clinicopathological factors including age, sex and pathological stage in 168 NPC patients. The staining intensity and distribution varied among the samples (Fig 2A), and a cutoff value according to the ROC curve was used to separate patients into two groups: a low KLHDC4 group (score ≤4.5, N = 103) and a high KLHDC4 group (score >4.5, N = 65). As shown in Table 2, KLHDC4 expression was significantly correlated with T classification (P = 0.016), N classification (P = 0.043) and total staging (P = 0.002). No difference was noted in KLHDC4 expression when stratified by gender (P = 1.000), age (P = 0.754), or M stage (P = 0.300). The Kaplan-Meier survival curves showed that the patients with high KLHDC4 expression had a significantly poorer overall survival (OS) and metastasis-free survival (MFS) when compared with patients with low KLHDC4 expression, as defined by the log-rank test (P = 0.005, Fig 2B; P = 0.012, Fig 2C).

Bottom Line: Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining.In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis.Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

ABSTRACT
Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

Show MeSH
Related in: MedlinePlus