Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer

Abstract

Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population.

ΗΙF1α, EGR1 and SP1 co-regulate the erythropoietin receptor expression under hypoxia: an essential role in the growth of non-small cell lung cancer cells

“…6a, b and Additional file 2: Table S4, SP1 was upregulated whereas EGR1 was downregulated in the NSCLC specimens as compared with the normal lung tissues. We also found that phosphor-EPO-R (pEPO-R) and HIF1α were also significantly higher in NSCLC, which is consistently with our previous report [17]. The expression levels of pEPO-R, HIF1α and SP1 were positively while EGR1 was negatively associated in NSCLC (Fig.…”

“…On the other hand, no significant EPO-R expression was detected in several systematic screenings in both tumor cell lines and solid tumor specimens [21, 22]. In NSCLC, we previously identified high- and low-EPO-R cell population and we found that tumor-derived EPO significantly stimulated the growth of EPO-R-positive NSCLC cells [17]. Here in this study, we further confirmed that EPO-R expression was inducible under hypoxia (independent of basal expression level) in NSCLC.…”

“…We previously reported that hypoxia can induce EPO expression and promote cell proliferation in NSCLC [17]. In the present study, we aim to investigate if and how hypoxia regulates EPO-R expression in NSCLC, and to determine if the transcription regulation of EPO-R has clinical relevance in NSCLC.…”

Erythropoietin Receptor is a Risk Factor for Prognosis: A Potential Biomarker in Lung Adenocarcinoma

“…On the one hand, high EPOR expression in locally advanced squamous cell carcinoma of the head and neck was considered to be an independent prognostic factor for OS and was associated with poorer OS [35], and activation of EPOR in melanoma was thought to promote tumor progression and contributed to survival of tumor cells [52], meanwhile, inhibition of EPOR gene expression in NSCLC reduced the growth of NSCLC cells under hypoxia [53]; on the one hand, there was no signi cant difference in survival rates between patients with different EPOR expression in gastric and cervical adenocarcinoma [28,36]; on the other hand, recurrence-free survival was signi cantly improved in ER+/EPOR+ breast cancer patients with untreated tamoxifen in breast cancer [54], and in the breast cancer cell lines, RAMA 37 cells (low EPOR expression) had a stronger proliferation ability than RAMA 37-28 cells (high EPOR expression), suggesting that high EPOR expression can reduce the ability of cells to divide [55], in addition, high levels of EPOR mRNA in myeloma were associated with better survival [37]. In some data, EPO/EPOR co-expression or co-overexpression in NSCLC was associated with poor prognosis [38][39][40], but independent evidence on the prognostic impact of EPOR on patients was lacking.…”

Erythropoietin receptor is a risk factor for prognosis: a potential biomarker in lung adenocarcinoma

“…On the one hand, high EPOR expression in locally advanced squamous cell carcinoma of the head and neck was considered to be an independent prognostic factor for OS and was associated with poorer OS [35], and activation of EPOR in melanoma was thought to promote tumor progression and contributed to survival of tumor cells [52], meanwhile, inhibition of EPOR gene expression in NSCLC reduced the growth of NSCLC cells under hypoxia [53]; on the one hand, there was no signi cant difference in survival rates between patients with different EPOR expression in gastric and cervical adenocarcinoma [28,36]; on the other hand, recurrence-free survival was signi cantly improved in ER+/EPOR+ breast cancer patients with untreated tamoxifen in breast cancer [54], and in the breast cancer cell lines, RAMA 37 cells (low EPOR expression) had a stronger proliferation ability than RAMA 37-28 cells (high EPOR expression), suggesting that high EPOR expression can reduce the ability of cells to divide [55], in addition, high levels of EPOR mRNA in myeloma were associated with better survival [37]. In some data, EPO/EPOR co-expression or co-overexpression in NSCLC was associated with poor prognosis [38][39][40], but independent evidence on the prognostic impact of EPOR on patients was lacking. Our results…”