Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), malignancies arising primarily in immunocompromised patients particularly AIDS-patients, while which are still lack of effective therapy. Hyaluronan (HA) is a large glucuronic acid and has been found closely related to multiple functions in cancer cells, although its role in viral oncogenesis remains largely unknown. Here we provide first evidence that KSHV de novo infection induces HA production from primary endothelial cells through upregulation of HA synthase gene 1 (Has1) and a multifunctional glycoprotein, CD147. Further data demonstrate that KSHV-induced HA production requires viral latent protein, LANA (in particular functional domain A) and MAPK/ERK signaling activities. In functions, HA production is necessary for KSHV/LANA-induced primary endothelial cell invasion, a hallmark feature for KS development. For clinical relevance, our data indicate that KSHV+ group has higher levels of HA and Has1 activities in their plasma than the KSHV- group of cohort HIV-infected patients. Together, our findings provide innovative insights into the mechanisms of oncogenic virus activation of HA production and its role in virus-associated malignancies pathogenesis, which may help to develop novel therapeutic strategies by targeting HA and related signaling.

Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression

“…Burkitt's lymphoma cell lines BL-41 (KSHV neg /EBV neg ), Akata and Mutu (both KSHV neg /EBV + ) were kindly provided by Dr. Dean Kedes (University of Virginia) and Dr. Erik Flemington (Tulane University), respectively, and cultured as described elsewhere [ 35 ]. Primary human umbilical vein endothelial cells (HUVEC) were cultured as described previously [ 36 ]. All experiments were carried out using cells harvested at low (<20) passages.…”

The CD147‐HYALURONAN Axis in Cancer

“…Experimental upregulation of CD147 stimulates message levels for all three hyaluronan synthases (HAS1, HAS2, and HAS3), leading to increased hyaluronan synthesis in various human cancer cell types (Marieb et al, ; Ghatak et al, ; Grass et al, ; Dai et al, ). The mechanism whereby CD147 regulates hyaluronan production is not yet clear but one possibility is related to accumulation of lactate via aerobic glycolysis (“the Warburg effect”), which is a common feature of aggressive tumors.…”

“…CD147 also promotes the mesenchymal phenotype by increasing hyaluronan synthesis (Marieb et al, ; Grass et al, ; Dai et al, ). Experimental overexpression of CD147 induces anchorage‐independent growth in nonmalignant breast epithelial cells by a process that is dependent on hyaluronan–receptor interactions (Marieb et al, ).…”

“…Kaposi's sarcoma “spindle” cells are derived from endothelial cells (Cancian et al, ; Ojala and Schulz, ), and we have shown that KSHV induces CD147 expression in primary human endothelial cells, which in turn promotes synthesis of several MMPs and onset of invasiveness (Qin et al, ; Dai et al, ). KSHV also stimulates HAS1 expression and hyaluronan synthesis in primary human endothelial cells by a CD147‐dependent mechanism involving stimulation of MAPK/ERK signaling activities (Dai et al, ). Invasiveness in the KSHV‐infected endothelial cells is dependent on both CD147 and hyaluronan (Dai et al, ; Dai et al, ).…”

“…KSHV also stimulates HAS1 expression and hyaluronan synthesis in primary human endothelial cells by a CD147‐dependent mechanism involving stimulation of MAPK/ERK signaling activities (Dai et al, ). Invasiveness in the KSHV‐infected endothelial cells is dependent on both CD147 and hyaluronan (Dai et al, ; Dai et al, ).…”