HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.

HER4 promotes the progression of colorectal cancer by promoting epithelial‑mesenchymal transition

“…Metastasis is a critical factor in the prognosis of patients with tumors (33). in osteosarcoma, knockdown of Her4 inhibits proliferation and tumorigenesis, induces apoptosis both in vitro and in vivo, and enhances the sensitivity to the chemotherapeutics methotrexate and doxorubicin (11). The present results showed that silencing of Her4 expression decreased proliferation and increased apoptosis of HcT116 cells, indicating that Her4 may be a valuable biomarker and potential target for crc therapy.…”

“…Her4 regulates cell proliferation, survival and differentiation, and is expressed both in fetal and normal tissues (4). an increasing number of studies have demonstrated that Her4 may be involved in tumorigenesis (9)(10)(11). nielsen et al (10) found that Her4 expression is associated with short progression-free survival in malignant melanoma.…”

“…nielsen et al (10) found that Her4 expression is associated with short progression-free survival in malignant melanoma. Wang et al (11) showed that Her4 expression promotes osteosarcoma cell proliferation and tumorigenesis, and reduced apoptosis both in vitro and in vivo. in our previous study, cYT-2, but not cYT-1, could significantly promote CRC progression (12).…”

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

“…Recent studies have suggested that induction of cellular senescence is a promising strategy for enhancing therapeutic efficacy in various cancers, including OS [23,25,40]. We then explored whether PRMT5 plays a role in regulating senescence of OS cells with or without the DNA damaging stress elicited by the most common first-line chemotherapeutic drug, CDDP.…”

Peptide KRP Conjugated with Doxorubicin Exerts Anti-Tumor Activity by Regulating RPS6KA2 in Osteosarcoma

“…Currently available drugs are limited by their ability to penetrate the cell, which could be the reason for their low biological activity, low therapeutic e cacy, and enhanced toxicity (Wang et al, 2018).…”