Decreased HCRP1 promotes breast cancer metastasis by enhancing EGFR phosphorylation.

Previous study showed that hepatocellular carcinoma related protein 1 (HCRP1) is decreased in breast cancer. HCRP1 expression is inversely related to epithelial growth factor receptor (EGFR) in breast cancer tissues, and patients with breast cancer expressing lower HCRP1 tended to suffer a shorter life expectancy. However, the detailed biological functions of HCRP1 in breast cancer as well as the interaction between HCRP1 and EGFR remain unexplored. In this study, we examined HCRP1 expression in breast cancer tissues and cell lines by western blot. Thereafter, we performed transwell migration and matrigel invasion assays after siRNA interference and lentiviral vector of HCRP1 infection. To further investigate the interaction between HCRP1 downregulation and EGFR signaling pathway, we evaluated the phosphorylation status of EGFR, Erk1/2 and Akt by western blot following HCRP1-siRNA transfection. Moreover, we investigated the in vivo functions of HCRP1 using a breast cancer xenograft model. We found that HCRP1 depletion significantly promoted breast cancer migration and invasion while HCRP1 overexpression produced an opposite effect. In addition, HCRP1 depletion decreased EGFR degradation and enhanced phosphorylation of EGFR. Interestingly, HCRP1 depletion also led to insensitivity to EGFR inhibitors treatment. The in vivo experiment confirmed the metastasis inhibition function of HCRP1. The present data indicate that HCRP1 inhibits breast cancer metastasis through downregulating EGFR phosphorylation.

HCRP1 is downregulated in non-small cell lung cancer and regulates proliferation, invasion, and drug resistance.

HCRP1 has been reported to have tumor suppressive function. However, its expression pattern and function in human non-small cell lung cancer (NSCLC) remain obscure. This study aims to explore clinical significance of HCRP1 in NSCLC. Immunohistochemical results showed high HCRP1 protein in normal bronchial epithelial tissue and downregulated HCRP1 expression in 47/98 lung cancer specimens. HCRP1 downregulation correlated with clinical stage (p = 0.0203), nodal status (p = 0.0168), and poor patient prognosis (log-rank, p = 0.0076). Univariate analysis showed that TNM stage (p < 0.0001) and HCRP1 (p = 0.0098) were significant prognostic factors; Cox regression model showed that TNM stage serves as an independent prognostic factor (p = 0.0011). We also found that HCRP1 was downregulated in lung cancer cells compared with normal HBE cells. HCRP1 plasmid transfection in H1299 cells inhibited proliferation, cell cycle progression, and invasion. HCRP1 depletion in A549 cells showed the opposite biological effects. In addition, we found that HCRP1 could inhibit MAPK and AKT signaling with downregulation of ERK and AKT phosphorylation, cyclin proteins, Bcl2 and MMP9, while HCRP1 depletion activated ERK and AKT signaling. The level of EGFR phosphorylation was also inhibited by HCRP1. In addition, we found that HCRP1 depletion confers multidrug resistance in H1299 cells. We employed paclitaxel and cisplatin in A549 cells with HCRP1 depletion. HCRP1 depletion decreased the effect of paclitaxel and cisplatin in A549 cells. Treatment with EGFR inhibitor AG1478 and AKT inhibitor LY249004 abolished the effect of HCRP1 depletion on drug resistance. In conclusion, the present study demonstrate that HCRP1 is downregulated in NSCLC and regulates proliferation, invasion, and drug resistance through modulation of EGFR signaling.

HCRP1 expression status is a significant prognostic marker in oral and oropharyngeal cancer.

OBJECTIVE: The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS: HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses. RESULTS: Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02). CONCLUSION: Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy.

HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer.

Prostate cancer (PCa) is the third leading malignancy engendering mortality among men globally. The present study aimed at determining the expression of hepatocellular carcinoma-related protein-1 (HCRP-1) in PCa, to explore its potential role in prostate tumorigenesis in vitro and in vivo. We evaluated HCRP-1 protein with immunohistochemistry (IHC) technology and found HCRP-1 expression was significantly low in PCa tissues (PCTs); In addition, the decreased HCRP-1 was significantly associated with TNM (tumor node metastasis) stage, advanced histology grade and gleason score. Transwell, tube formation, Western blot and co-immunoprecipitation (Co-IP) assays were utilized to determine the role of down-regulating HCRP-1 in PCa cell migration, invasion and angiogenesis. Meanwhile, we found HCRP-1 depletion induced Src and focal adhesion kinase (FAK) phosphorylation, which could be reversed by Src inhibitor PP2 or FAK inhibitor. Furthermore, down-regulated HCRP-1 evidently induced lung metastasis of PCa cells in xenograft mode. Taken together, our study indicates HCRP-1 plays an important role in PCa metastasis. HCRP-1 may serve as a potential therapeutic target for PCa.

HCRP1 inhibits cell proliferation and invasion and promotes chemosensitivity in esophageal squamous cell carcinoma.

Hepatocellular carcinoma related protein 1 (HCRP1), which is essential for internalization and degradation of ubiquitinated membrane receptors, was reported to play crucial roles in cancer pathogenesis and progression. However, the functional roles of HCRP1 in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we investigated the effects of HCRP1 on ESCC cells and the underlying mechanism. Our results demonstrated that HCRP1 was lowly expressed in ESCC tissues and cell lines. Overexpression of HCRP1 significantly suppressed ESCC cell proliferation and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, HCRP1 increased the sensitivity of ESCC cells towards cisplatin/fluorouracil. Mechanistically, HCRP1 inhibited the activity of Wnt/ß-catenin signaling pathway in ESCC cells. In conclusion, these findings indicated that HCRP1 suppressed ESCC cell proliferation and invasion through regulation of the Wnt/ß-catenin pathway. Therefore, HCRP1 may function as a tumor suppressor in ESCC progression.

HCRP1, ID4 and Glypican-3: an optimal panel of biomarkers for diagnosis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with high morbidity and mortality. The aim of this study was to assess the diagnostic role of HCC related protein 1 (HCRP1) and inhibitor of DNA Binding 4 (ID4) as novel reliable markers for HCC diagnosis. METHODS: Immunohistochemistry for HCRP1, ID4 and Glypican-3 (GPC-3) was performed in 98 cases of HCCs, 15 large regenerative nodules arising in cirrhotic livers, 12 hepatocellular adenomas (HCA), 10 focal nodular hyperplasias (FNH), and 20 specimens of normal liver tissues (NL). RESULTS: HCRP1 immunoactivity was decreased in 64 of 98 (65.3%) HCC cases but present in almost all of the benign liver nodules (56/57, 98.2%, P < 0.001). 68 of 98 (69.4%) and 70 of 98 (71.4%) HCC cases were positive for ID4 and GPC-3, respectively, which were much higher than in benign lesions. Even though HCRP1 is highly specific (98.25%) in differentiating well differentiated HCC (WDHCC) from benign liver nodules, it has only a limited value because of its low sensitivity (37.5%), neither for the ID4, GPC-3 alone or combination (P > 0.05). The expression of HCRP1 alone could efficiently distinguish WDHCC from moderate-poorly differentiated HCC (M-PHCC), and the combination of using either two or three markers could notably increase the diagnosis accuracy (P < 0.05). CONCLUSION: HCRP1 and ID4 represent potentially novel valuable biomarkers for distinguishing HCC from benign liver nodules, and it is recommended to use the combination of HCRP1, ID4 and GPC-3 as a panel in HCC differentiation estimation.

HCRP1 downregulation confers poor prognosis and induces chemoresistance through regulation of EGFR-AKT pathway in human gastric cancer.

The current study aims to investigate the biological roles and clinical significance of HCRP1 in human gastric cancer. The expression pattern of HCRP1 in gastric cancer tissue and adjacent non-cancerous tissue was detected by immunohistochemistry. HCRP1 downregulation was found in 57 of 137 human gastric cancer samples and correlated with advanced TNM stage, positive nodal status, and relapse. Log-rank test showed that HCRP1 downregulation also correlated with poor overall survival and reduced relapse-free survival. In addition, we found that HCRP1 overexpression inhibited proliferation, colony formation, and invasion in HGC-27 cells. On the other hand, HCRP1 depletion by small interfering RNA promoted proliferation, colony formation, and invasion in SGC-7901 cells. We also treated gastric cancer cells with cisplatin. MTT and Annexin V/PI analysis were carried out to examine change of chemoresistance. We found that HCRP1 overexpression sensitized HGC-27 cells to cisplatin while its depletion reduced sensitivity in SGC-7901 cells. Moreover, we found that HCRP1 overexpression negatively regulated cyclin D1, MMP-2, p-EGFR, p-ERK, and p-AKT. HCRP1 depletion showed the opposite effects. In conclusion, our results suggest that HCRP1 downregulation might serve as an indicator for poor prognosis in gastric cancer patients. HCRP1 reduces drug resistance through regulation of EGFR-AKT signaling.

HCRP1 regulates proliferation, invasion, and drug resistance via EGFR signaling in prostate cancer.

Previous studies showed that HCRP1 is decreased in tumor cells compared with normal tissue, and functions as a tumor suppressor. However, its expression pattern and function in human prostate cancer remain unclear. In this study we examined HCRP1 expression in prostate cancer cell lines via western blotting. Thereafter, we performed CCK-8 assay and matrigel invasion assay after cells were transfected with HCRP1 overexpression plasmid or siRNA. We further investigated the possible mechanism involved in HCRP1's regulation to prostate cancer cell proliferation and invasion. We found that HCRP1 negatively regulates EGFR activity and expression of its downstream proteins. Moreover, we found that HCRP1 is negatively correlated with multi-drug resistant related proteins after cells were treated with paclitaxel, cisplatin or gefitinib, indicating its inhibiting effect of chemotherapy resistance. In summary, our results provided evidence that HCRP1 is a negative regulator in prostate cancer progression, metastasis and multi-drug resistance.

Up-regulation of HCRP1 inhibits proliferation and invasion in glioma cells via suppressing the ERK and AKT signaling pathways.

Hepatocellular carcinoma-related protein 1 (HCRP1), also known as the homologue of vacuolar protein sorting 37A (hVps37A), serves as a membrane trafficking complex to mediate internalization and degradation of ubiquitinated membrane receptors. Recently, more and more researchers have showed that HCRP1 plays a critical role in tumorigenesis. However, the biological roles of HCRP1 in glioma remain to be elucidated. In the present study, we detected the expression pattern of HCRP1 in glioma. The results showed that HCRP1 was significantly down-regulated in glioma tissues and cell lines. On the basis of further analysis, we demonstrated that up-regulation of HCRP1 efficiently inhibited glioma cell proliferation and invasion in vitro, and as well as suppressed glioma cell growth in vivo. In addition, we found that HCRP1 up-regulation decreased the levels of p-ERK and p-AKT in glioma cells. We also emphasized that the ERK and AKT signaling pathways were the mechanisms underlying the inhibitory effect of HCRP1 on glioma cells. Taken together, we provided evidence in support of the prognostic value of HCRP1 in glioma and suggested it as a promising target for glioma treatment.

Decreased HCRP1 expression is associated with poor prognosis in breast cancer patients.

BACKGROUND: Downregulation of hepatocellular carcinoma related protein 1 (HCRP1) has been reported to be associated with a poor prognosis in a variety of malignant tumors. The purpose of this study was to assess HCRP1 expression in breast cancer and to examine its possible correlation with commonly used prognostic factors, particularly epidermal growth factor receptor (EGFR). METHODS: Immunohistochemical analysis was performed on tumors from 194 patients with primary breast cancer. HCRP1 expression was analyzed along with major clinicopathological variables. RESULTS: HCRP1 protein expression was shown to be correlated with age (P = 0.001), histological grade (P = 0.005), tumor progression (P = 0.013), and death (P = 0.001), but not with tumor size, lymph-node metastasis, or Ki67 status. Kaplan-Meier survival curves showed that lower HCRP1 expression was significantly correlated with increased short-term survival (P < 0.001), and both univariate and multivariate analyses revealed that HCRP1, tumor size, lymph-node metastasis, and human epidermal growth factor receptor-2 (HER-2) were independent prognostic factors (all P < 0.05). In addition, low HCRP1 expression was much more frequent in triple negative breast cancer (TNBC; 63.89%) than in luminal (16.95%) and HER-2 overexpression phenotypes (7.5%; P < 0.001), and significant correlations between HCRP1 and survival time were observed for the TNBC group (P < 0.004). Furthermore, an inverse relationship between HCRP1 and EGFR expression was found both for the complete set of all cases (P < 0.001), and for each phenotype analyzed individually (P < 0.05). CONCLUSION: Our results suggest that HCRP1 may play an important role in EGFR regulation and that its decreased expression is an independent predictor of breast cancer, especially in TNBC patients.