Expression and clinical significance of HIF-1α/SHH signaling pathway in neuroblastoma

doi:10.3969/j.issn.1674-8115.2021.08.010

Abstract

Abstract: Objective

·To investigate the expression and clinical significance of hypoxia inducible factor-1α (HIF-1α)/sonic hedgehog (SHH) signaling pathway in neuroblastoma (NB).

Methods

·The expressions of HIF-1α and SHH in paraffin sections of 101 NB cases and 20 ganglioneuroma (GN) cases were analyzed by immunohistochemistry. The differences in the expression levels of these two proteins were compared between NB and GN. And correlations between HIF-1α/SHH expression levels and NB patients′ clinicopathological characteristics or prognosis were analyzed.

Results

·The expression levels of HIF-1α and SHH in NBs were significantly higher than those in GNs (HIF-1α: 26.7% vs 5.0%, P=0.035; SHH: 32.7% vs 10.0%, P=0.041). Compared with low-stage (stage 1 and 2) NBs or NBs with favorable histology, HIF-1α and SHH expression levels were significantly higher in high-stage (stage 3 and 4) NBs or NBs with unfavorable histology (HIF-1α: P=0.002 and 0.012, respectively; SHH: P=0.021 and 0.007, respectively). The expression levels of these two proteins were also higher in NBs with local lymph node metastasis (HIF-1α: P=0.012; SHH: P=0.001). A significant positive correlation was found between HIF-1α and SHH expression levels in NB specimens (r=0.41, P=0.000). The 5-year overall survival (OS) rate and event-free survival (EFS) rate of the HIF-1α high-expression group were significantly lower than those of the HIF-1α low-expression group(OS rate: 40.9% vs 75.7%, P=0.001; EFS rate: 40.9% vs 70.0%, P=0.008). The 5-year OS rate and EFS rate of the SHH high-expression group were also significantly lower than those of the SHH low-expression group (OS rate: 42.9% vs 78.1%, P=0.000; EFS rate: 39.3% vs 73.4%, P=0.001).

Conclusion

·The increased expressions of HIF-1α and SHH in NB are closely related to clinical features of NB, such as stage, local lymph node metastasis and unfavorable histology, and indicate the poor prognosis. Hence, HIF-1α/SHH signal pathway might be a potential biomarker and therapeutic target for NB.

Key words: neuroblastoma (NB), hypoxia inducible factor-1α (HIF-1α), sonic hedgehog (SHH), prognosis, immunohistochemistry

CLC Number:

R739.43

Sheng CHEN, Zhi-long YAN, Ye-ming WU, Min XU, Song GU, Jing MA. Expression and clinical significance of HIF-1α/SHH signaling pathway in neuroblastoma[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1056-1061.

Figures/Tables 4

TrendMD

References 23

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Expression	NB （n=101）	GN （n=20）	P value
HIF-1α/n（%）			0.035
High	27 （26.7）	1 （5.0）
Low	74 （73.3）	19 （95.0）
SHH/n（%）			0.041
High	33 （32.7）	2 （10.0）
Low	68 （67.3）	18 （90.0）

Expression	NB （n=101）	GN （n=20）	P value
HIF-1α/n（%）			0.035
High	27 （26.7）	1 （5.0）
Low	74 （73.3）	19 （95.0）
SHH/n（%）			0.041
High	33 （32.7）	2 （10.0）
Low	68 （67.3）	18 （90.0）

Index	HIF-1α			SHH
Index	High expression （n=27）	Low expression （n=74）	P value	High expression （n=33）	Low expression （n=68）	P value
Age/n（%）			0.310			0.327
<3 year	18 （30.5）	41 （69.5）		17 （28.8）	42 （71.2）
≥3 year	9 （21.4）	33 （78.6）		16 （38.1）	26 （61.9）
Gender/n（%）			0.202			0.067
Male	17 （32.1）	36 （67.9）		13 （24.5）	40 （75.5）
Female	10 （20.8）	38 （79.2）		20 （41.7）	28 （58.3）
Stage/n（%）			0.002			0.021
1， 2	5 （11.4）	39 （88.6）		9 （20.5）	35 （79.5）
3， 4	22 （38.6）	35 （61.4）		24 （42.1）	33 （57.9）
Pathological type/n（%）			0.012
FH	7 （14.9）	40 （85.1）		9 （19.1）	38 （80.9）	0.007
UFH	20 （37.0）	34 （63.0）		24 （44.4）	30 （55.6）
MYCN amplification/n（%）			0.079			1.000
Yes	6 （50.0）	6 （50.0）		4 （33.3）	8 （66.7）
No	21 （23.6）	68 （76.4）		29 （32.6）	60 （67.4）
Local lymph node metastasis/n（%）			0.012			0.001
Yes	21 （36.2）	37 （63.8）		27 （46.6）	31 （53.4）
No	6 （14.0）	37 （86.0）		6 （14.0）	37 （86.0）
Distant metastasis/n（%）			0.113			0.584
Yes	13 （36.1）	23 （63.9）		13 （36.1）	23 （63.9）
No	14 （21.5）	51 （78.5）		20 （30.8）	45 （69.2）

Index	HIF-1α			SHH
Index	High expression （n=27）	Low expression （n=74）	P value	High expression （n=33）	Low expression （n=68）	P value
Age/n（%）			0.310			0.327
<3 year	18 （30.5）	41 （69.5）		17 （28.8）	42 （71.2）
≥3 year	9 （21.4）	33 （78.6）		16 （38.1）	26 （61.9）
Gender/n（%）			0.202			0.067
Male	17 （32.1）	36 （67.9）		13 （24.5）	40 （75.5）
Female	10 （20.8）	38 （79.2）		20 （41.7）	28 （58.3）
Stage/n（%）			0.002			0.021
1， 2	5 （11.4）	39 （88.6）		9 （20.5）	35 （79.5）
3， 4	22 （38.6）	35 （61.4）		24 （42.1）	33 （57.9）
Pathological type/n（%）			0.012
FH	7 （14.9）	40 （85.1）		9 （19.1）	38 （80.9）	0.007
UFH	20 （37.0）	34 （63.0）		24 （44.4）	30 （55.6）
MYCN amplification/n（%）			0.079			1.000
Yes	6 （50.0）	6 （50.0）		4 （33.3）	8 （66.7）
No	21 （23.6）	68 （76.4）		29 （32.6）	60 （67.4）
Local lymph node metastasis/n（%）			0.012			0.001
Yes	21 （36.2）	37 （63.8）		27 （46.6）	31 （53.4）
No	6 （14.0）	37 （86.0）		6 （14.0）	37 （86.0）
Distant metastasis/n（%）			0.113			0.584
Yes	13 （36.1）	23 （63.9）		13 （36.1）	23 （63.9）
No	14 （21.5）	51 （78.5）		20 （30.8）	45 （69.2）

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