The expression of DAMP proteins HSP70 and cancer-testis antigen SPAG9 in peripheral blood of patients with HCC and lung cancer

Ren, Baizhao; Luo, Shudi; Xu, Fei; Zou, Guoying; Xu, Guofeng; He, Junyu; Huang, Yiran; Zhu, Hongli; Li, Yong

doi:10.1007/s12192-016-0758-5

Cited by 25 publications

(21 citation statements)

References 33 publications

(31 reference statements)

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“…We also detected a high expression of HSP70 and TLR4 in cancer tissues of patients with liver cancer. Our previous study revealed that the serum HSP70 levels in patients with hepatitis cirrhosis, as well as in patients with liver cancer, were higher than normal (19). These findings revealed that DAMP HSP70 is associated with the pathological process both of inflammation and cancer.…”

Section: Discussionmentioning

confidence: 89%

Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

et al. 2018

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Curcumin has been revealed to inhibit liver cancer, however, no studies have reported that the mechanism of curcumin's action on liver cancer is related to damage-associated molecular pattern (DAMP) molecules heat shock protein 70 (HSP70) and the toll-like receptor 4 (TLR4) signaling. This study aimed to investigate whether the activation of TLR4 signaling by HSP70 could be inhibited by curcumin, thus investigating the possible mechanism of curcumin in the inhibition of liver cancer. Western blotting was used to evaluate the expression of the HSP70 and TLR4 in HepG2 cells and ELISA was used to detect the concentration of HSP70 in cell culture medium. A thermal tolerance HepG2 (HepG2TT) cell model was established to simulate HSP70 accumulation in the microenvironment. A certain concentration of curcumin was co-cultured with HepG2 and HepG2TT cells to observe the changes of HSP70 and TLR4. Our results revealed that heat stress significantly increased the expression of extracellular HSP70 (eHSP70) and TLR4 (P<0.01), but significantly reduced the expression of intracellular HSP70 (P<0.01). Curcumin inhibited proliferation, invasion, and metastasis of HepG2 cells, caused cells to remain in the DNA S phase, promoted apoptosis, and significantly reduced intracellular HSP70, eHSP70 and TLR4 levels of HepG2TT cells. Following the removal of curcumin, eHSP70 increased again. In summary, our results demonstrated that the antitumor effect of curcumin was related to the inhibition HSP70-TLR4 signaling.

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Section: Discussionmentioning

confidence: 89%

Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

et al. 2018

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“…Elevated serum Hsp70 and Hsp90 have been reported in patients with cachexia-prone cancers including lung 42 – 47 , colorectal 48 and pancreatic cancer 49 , but not in patients with breast cancer 50 that is not highly prone to cachexia. Importantly, serum Hsp70 and Hsp90 levels in cancer patients increase with the development of pathological grade and clinical stage 43 , 44 , 46 , and the increase correlates with mortality in cancer patients 42 , 48 , to which cachexia is a major determinant.…”

Section: Discussionmentioning

confidence: 99%

“…However, these clinical studies did not examine whether elevation in serum Hsp70/90 and EVs correlated with cachexia. Because at least partially that non-standardized assays were used in these clinical studies, the reported values of basal serum Hsp70 in humans vary from 0.04 49 to 8.5 ng/ml 47 , and basal serum Hsp90α levels vary from 17 50 to 40 ng/ml 43 . The basal serum Hsp70 levels we measured in mice (~3 ng/ml, Fig.…”

Section: Discussionmentioning

confidence: 99%

Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90

et al. 2017

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Cachexia, characterized by muscle wasting, is a major contributor to cancer-related mortality. However, the key cachexins that mediate cancer-induced muscle wasting remain elusive. Here, we show that tumor-released extracellular Hsp70 and Hsp90 are responsible for tumor’s capacity to induce muscle wasting. We detected high-level constitutive release of Hsp70 and Hsp90 associated with extracellular vesicles (EVs) from diverse cachexia-inducing tumor cells, resulting in elevated serum levels in mice. Neutralizing extracellular Hsp70/90 or silencing Hsp70/90 expression in tumor cells abrogates tumor-induced muscle catabolism and wasting in cultured myotubes and in mice. Conversely, administration of recombinant Hsp70 and Hsp90 recapitulates the catabolic effects of tumor. In addition, tumor-released Hsp70/90-expressing EVs are necessary and sufficient for tumor-induced muscle wasting. Further, Hsp70 and Hsp90 induce muscle catabolism by activating TLR4, and are responsible for elevation of circulating cytokines. These findings identify tumor-released circulating Hsp70 and Hsp90 as key cachexins causing muscle wasting in mice.

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“…In addition, we also showed humoral response against SPAG9 in various histotypes of ovarian cancer patients. 9 Recently, SPAG9 has also been shown to generate strong humoral response in hepatocellular carcinoma and lung cancer patients, 13 indicating its therapeutic potential as a tumor-specific biomarker for cancer management. In present investigation, our data show that ablation of SPAG9 in ovarian cancer cells resulted in increased DNA damage, cell cycle arrest, apoptosis, reduction in cellular migration and invasion ability in in vitro and reduced ovarian tumor growth in human xenograft mouse model.…”

Section: Discussionmentioning

confidence: 99%

Sperm associated antigen 9 (SPAG9) a promising therapeutic target of ovarian carcinoma

et al. 2018

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SPAG9 is a novel tumor associated antigen, expressed in variety of malignancies. However, its role in ovarian cancer remains unexplored. SPAG9 expression was validated in ovarian cancer cells by real time PCR and Western blot. SPAG9 involvement in cell cycle, DNA damage, apoptosis, paclitaxel sensitivity and epithelial- mesenchymal transition (EMT) was investigated employing RNA interference approach. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro. Quantitative PCR and Western blot analysis revealed SPAG9 expression in A10, SKOV-3 and Caov3 compared to normal ovarian epithelial cells. SPAG9 ablation resulted in reduced cellular proliferation, colony forming ability and enhanced cytotoxicity of chemotherapeutic agent paclitaxel. Effect of ablation of SPAG9 on cell cycle revealed S phase arrest and showed decreased expression of CDK1, CDK2, CDK4, CDK6, cyclin B1, cyclin D1, cyclin E and increased expression of tumor suppressor p21. Ablation of SPAG9 also resulted in increased apoptosis with increased expression of various pro- apoptotic molecules including BAD, BID, PUMA, caspase 3, caspase 7, caspase 8 and cytochrome C. Decreased expression of mesenchymal markers and increased expression of epithelial markers was found in SPAG9 ablated cells. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro assays which showed that ablation of SPAG9 resulted in increased paclitaxel sensitivity and caused enhanced cell death. In vivo ovarian cancer xenograft studies showed that ablation of SPAG9 resulted in significant reduction in tumor growth. Present study revealed therapeutic potential of SPAG9 in ovarian cancer.

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The expression of DAMP proteins HSP70 and cancer-testis antigen SPAG9 in peripheral blood of patients with HCC and lung cancer

Cited by 25 publications

References 33 publications

Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

Curcumin inhibits liver cancer by inhibiting DAMP molecule HSP70 and TLR4 signaling

Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90

Sperm associated antigen 9 (SPAG9) a promising therapeutic target of ovarian carcinoma

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