HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma

Abstract

Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is highly expressed in renal proximal tubules, where it contributes to the control of cell proliferation and differentiation. HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney injury. Sustained hyper-proliferation and de-differentiation are important hallmarks of tumor progression. Here, we demonstrate that cancer cells overexpressing HCaRG maintain a more differentiated phenotype, while several of them undergo autophagic cell death. Its overexpression in mouse renal cell carcinomas led to smaller tumor size with less tumor vascularization in a homograft tumor model. Mechanistically, HCaRG promotes de-phosphorylation of the proto-oncogene erythroblastosis oncogene B (ErbB)2/HER2 and epigenetic gene silencing of epidermal growth factor receptor and ErbB3 via promoter methylation. Extracellular signal-regulated kinase, AKT and mammalian target of rapamycin which mediate ErbB-dowstream signaling pathways are inactivated by HCaRG expression. In addition, HCaRG is underexpressed in human renal cell carcinomas and more expressed in normal tissue adjacent to renal cell carcinomas of patients with favorable prognosis. Taken together, our data suggest a role for HCaRG in the inhibition of tumor progression as a natural inhibitor of the ErbB signals in cancer and as a potential prognostic marker for renal cell carcinomas.

Internal enhancement of DNA damage by a novel bispecific antibody‐drug conjugate‐like therapeutics via blockage of mTOR and PD‐L1 signal pathways in pancreatic cancer

“…The EGFR family (EGFR also known as HER) is a subset of receptor tyrosine kinases that activate and regulate diverse processes, including cell survival, proliferation, differentiation, and migration . It has been shown to be activated in many epithelial cancers such as colorectal, breast, and lung cancers .…”

miR372 Promotes Progression of Liver Cancer Cells by Upregulating erbB-2 through Enhancement of YB-1

“… 53 Moreover, erbB-2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway, 54 and HCaRG/COMMD5 inhibits erbB-receptor-driven renal cell carcinoma. 55 Moreover, ERRF sensitizes erbB-2-positive breast cancer cells to lapatinib treatment likely by attenuating MCL1 and ERBB2 expression. 56 In addition, overexpression of erbB-2 has been implicated in the pathogenesis of cholangiocarcinoma, suggesting that combined erbB-2 targeting might serve as a target-based therapeutic strategy for this highly lethal cancer.…”

Does Subtelomeric Position of COMMD5 Influence Cancer Progression?

“…HCaRG was later shown to be COMMD5, the longest protein member of the COMMD family. Our studies demonstrated a role for COMMD5 in the establishment and maintenance of the epithelial cell phenotype, and suggested a tumor suppressor gene function (15,35,(37)(38)(39)(40)(41). COMMD5 levels are low in various cancer cell lines in rodents and humans (35)(36)(37)(38).…”

“…COMMD5 levels are low in various cancer cell lines in rodents and humans ( 35 – 38 ). We found that COMMD5 was underexpressed in human clear-cell renal cell carcinomas (CCRCCc) from 117 patients ( 39 ). Its expression was maintained in normal tissues adjacent to small renal tumors, while low expression was observed in normal adjacent tissues of larger size RCCs in patients with poor prognosis.…”

“…Its expression was maintained in normal tissues adjacent to small renal tumors, while low expression was observed in normal adjacent tissues of larger size RCCs in patients with poor prognosis. Low COMMD5 levels in normal tissues were associated with worse clinical outcome (recurrence-free survival curves/5 years of patients) ( 39 ). COMMD5/HCaRG overexpression inhibited tumor growth and angiogenesis in a homograft renal carcinoma mouse model by promoting de-phosphorylation of ErbB2/HER2, ErbB3/HER3, and EGFR, leading to inhibition of ErbB signaling pathways ( 39 ).…”