HTRA3 is Reduced in Ovarian Cancers Regardless of Stage

Zhao, Min; Ding, Jianxun; Nie, Guiying; Wei, Jia; Li, Yan; Xiong, Yin; Chen, Qi

doi:10.3109/07357907.2014.958496

Cited by 15 publications

(13 citation statements)

References 25 publications

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“…In breast cancer, the expression of HTRA3 was significantly lower in stage III than in stages I and II [19]. More recently, HTRA3 levels were found to correlate with the malignant subtypes of ovarian cancers [20]. Although the function of HTRA3 in lung cancer has not been fully identified, a previous study suggested that HTRA3 is a mitochondrial protease that promotes etoposide- and cisplatin-induced cytotoxicity by activating the apoptotic pathway [16].…”

Section: Discussionmentioning

confidence: 99%

High temperature requirement A3 (HTRA3) expression predicts postoperative recurrence and survival in patients with non-small-cell lung cancer

Zhao

Zhang

et al. 2016

Oncotarget

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Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, and its recurrence rate after complete resection is high, owing to local or distant metastases. Low expression of high temperature requirement A3 (HTRA3) has been reported to promote tumorigenesis, diminish the effects of anti-tumor treatments, and correlate with a malignant phenotype. To assess the involvement of HTRA3 in the prognosis of postoperative NSCLC, we obtained tumors from 78 patients who had undergone complete surgical resection, and immunohistochemically examined them for HTRA3 expression. HTRA3 was significantly down-regulated in lung cancer tissues compared with normal lung tissues, and only six tumor cases(7.7%) exhibited relatively high levels of HTRA3 (P < 0.001). Notably, high-HTRA3 patients were at significantly lower risk of postoperative recurrence than low-HTRA3 or HTRA3-negative patients (0% versus 31.2% and 35.0%; P = 0.044, 0.029, respectively). High expression of HTRA3 also independently indicated longer disease-free survival in Cox regression analysis (hazard ratio 0.39, 95%CI 0.16-0.95, P = 0.038). Ectopic expression of the long isoform of HTRA3 attenuated the invasion of an NSCLC cell line in a Transwell assay, while knockdown of HTRA3 had the converse effect. Thus, HTRA3 suppresses tumor cell invasiveness and may serve as a prognostic biomarker for postoperative recurrence or survival in NSCLC.

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Section: Discussionmentioning

confidence: 99%

High temperature requirement A3 (HTRA3) expression predicts postoperative recurrence and survival in patients with non-small-cell lung cancer

Zhao

Zhang

et al. 2016

Oncotarget

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“…HtrA3 is a protease involved in the promotion of apoptosis and embryo implantation [ 20 ] [ 22 ] [ 23 ] [ 25 ] and linked to human diseases such as cancer and preeclampsia [ 24 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ]. We sought structural and biochemical insights into its function, so that its role in physiological conditions and disease may be better understood.…”

Section: Discussionmentioning

confidence: 99%

“…HtrA3 was initially identified in the developing placenta as a serine protease associated with pregnancy [ 20 ] [ 21 ] [ 22 ] [ 23 ]. Dysregulation of HtrA3 has been observed in a number of diseases including cancer [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] and preeclampsia [ 31 ] [ 32 ]. Downregulation of HtrA3 was associated with the progression of endometrial and ovarian cancer [ 26 ] [ 27 ] [ 28 ] [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains

et al. 2015

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Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

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“…The 39-kDa short isoform (HTRA3-S) lacks the PDZ domain at the C-terminus and instead has a unique sequence of seven amino acids, which is encoded by a separate exon (10). Downregulation of HTRA3 is observed in several cancers (11,12). The underlying mechanisms for its reduction are not fully understood, but a lung cancer study proposed that it may be related to cigarette smoke-induced methylation within the first exon of HTRA3 (13).…”

Section: Introductionmentioning

confidence: 99%

Antagonism between HTRA3 and TGFβ1 Contributes to Metastasis in Non–Small Cell Lung Cancer

et al. 2019

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High temperature requirement A3 (HTRA3, long and short isoforms) is a member of the HtrA family and has been implicated as a tumor suppressor in cancer progression in multiple cancer types, yet its molecular functions in nonsmall cell lung cancer (NSCLC) are not well understood. Here, we report that decreased levels of HTRA3 negatively correlate with elevated TGFb1 in lung tumor tissue with metastasis. Furthermore, high expression of HTRA3 indicated better prognosis independent of TGFb1 expression. In NSCLC cell lines, exogenous TGFb1 significantly downregulated the level of HTRA3, especially the long isoform, during induction of epithelial-mesenchymal transition (EMT). Mechanistically, c-Jun, which is elevated by TGFb1, directly bound the promoter of HTRA3-L and inhibited its transcription. As a negative feedback loop, overexpression of HTRA3-L attenuated TGFb1-mediated invasion-metastasis cascades via activation of SMAD2/3 and sensitized cells to anti-PD-L1 treatment. Taken together, our findings suggest that in the early stages of cancer, overexpressed HTRA3 acts as a brake on the oncogenic effects of TGFb1 and inhibits tumor metastasis. In later stages, the role of HTRA3 is weakened and TGFb1 efficiently promotes EMT in the absence of the HTRA3 brake. Significance: This study provides new mechanistic insight of the interaction between HTRA3 and TGFb in lung cancer by illustrating that HTRA3 is a novel mediator acting as a suppressor of TGFb1-related oncogenic effects.

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HTRA3 is Reduced in Ovarian Cancers Regardless of Stage

Cited by 15 publications

References 25 publications

High temperature requirement A3 (HTRA3) expression predicts postoperative recurrence and survival in patients with non-small-cell lung cancer

High temperature requirement A3 (HTRA3) expression predicts postoperative recurrence and survival in patients with non-small-cell lung cancer

Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains

Antagonism between HTRA3 and TGFβ1 Contributes to Metastasis in Non–Small Cell Lung Cancer

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