Tumor Cell-Derived Microvesicles Induced Not Epithelial-Mesenchymal Transition but Apoptosis in Human Proximal Tubular (HK-2) Cells: Implications for Renal Impairment in Multiple Myeloma

Abstract

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target.

Microvesicles released from multiple myeloma cells are equipped with ectoenzymes belonging to canonical and non-canonical adenosinergic pathways and produce adenosine from ATP and NAD+

“…Zhao et al reported that MVs contribute to inducing renal function impairment in MM patients, by inducing apoptosis of proximal tubular cells. 23 Furthermore, MVs derived from MM cells induce neoplastic cell proliferation 24 and stimulate angiogenesis by inducing proliferation, tube formation, IL-6 secretion and VEGF release by endothelial cells. 33 The expression and function of adenosinergic ectoenzymes have been demonstrated on exosomes derived from cancer patients.…”

“…18,19 Tumor-derived EV are reported as involved in disease progression [20][21][22] and as dampening anti-tumor immune response. 17,18 Involvement of MVs in tissue damage 23 and disease progression. 24 was recently reported in MM patients.…”

PDTC inhibits apoptosis and phenotypic transformation of co-culture of myeloma cells and renal tubular epithelial cells by reducing the secretion of light chain protein

“…Sanders et al 22 reported that κ light chain protein can enter the nucleus and activate lysosomes, causing vacuoles and cell lysis, and eventually leading to apoptosis. Although there have been studies 4 showing that the cell activity of HK-2 was signi cantly decreased and apoptosis was signi cantly increased after treated with medium cultured with different MM cell lines, but renal pathogenic miRNA was found in the secretory vesicles of MM cell lines by sequencing. So whether the apoptosis of HK-2 cells is related to light-chain protein secreted by MM cell line has not been clari ed.…”

“…According to a study 4 , the cell viability of HK-2 cells treated with different MM cell lines was signi cantly decreased, and the apoptosis was also signi cantly increased. However, it was found by sequencing that the secretory vesicles of the MM cell line contain renal pathogenic miRNAs, and whether the apoptosis of HK-2 cells is related to the light chain protein secreted by the MM cell line has not been elucidated.It was reported that the light chain obtained in patients with end stage renal disease can enter HK-2 cells to produce su cient amount of hydrogen peroxide to stimulate the production of monocyte chemoattractant protein-1 (MCP-1), while MCP-1 is a key chemokine for proximal tubule activation 5 .…”

Vesicles bearing gifts: the functional importance of micro-RNA transfer in extracellular vesicles in chronic kidney disease

“…Tumor-derived EVs from the RPMI8226 multiple myeloma cell line have been shown to be enriched in a number of potentially proapoptotic miRs and promoted apoptosis in the human renal tubular cell line HK2 (162), leading the authors to suggest that such EVs may play a role in the renal impairment observed in multiple myeloma.…”