Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis.

BackgroundTo compare the effects of intraoperative infusions of balanced electrolyte solution (BES)-based hydroxyethyl starch (HES) and saline-based albumin on metabolic acidosis and acid/base changes during major abdominal surgery conducted using Stewart’s approach.MethodsForty patients, aged 20-65 years, undergoing major abdominal surgery, were randomly assigned to the HES group (n = 20; received 500 ml of BES-based 6% HES 130/0.4) or the albumin group (n = 20; received 500 ml of normal saline-based 5% albumin). Acid-base parameters were measured and calculated using results obtained from arterial blood samples taken after anesthesia induction (T1), 2 hours after surgery commencement (T2), immediately after surgery (T3), and 1 hour after arriving at a postanesthetic care unit (T4).ResultsArterial pH in the HES group was significantly higher than that in the albumin group at T3 (7.40 ± 0.04 vs. 7.38 ± 0.04, P = 0.043), and pH values exhibited significant intergroup difference over time (P = 0.002). Arterial pH was significantly lower at T3 and T4 in the HES group and at T2, T3, and T4 in the albumin group than at T1. Apparent strong ion difference (SIDa) was significantly lower at T2, T3, and T4 than at T1 in both groups. Total plasma weak nonvolatile acid (ATOT) was significantly lower in the HES group than in the albumin group at T2, T3 and T4 and exhibited a significant intergroup difference over time (P < 0.001).ConclusionsBES-based 6% HES infusion was associated with lower arterial pH values at the end of surgery than saline-based 5% albumin infusion, but neither colloid caused clinically significant metabolic acidosis (defined as an arterial pH < 7.35).

<p>PDF file - 65K, Regulation of the expression of various nuclear receptors by KSHV in BECs</p>

<p>PDF file - 91K, Regulation of the expression of the RGS genes by KSHV in BECs</p>

<p>PDF file - 91K, Regulation of the expression of the RGS genes by KSHV in BECs</p>

<p>PDF file - 65K, Regulation of the expression of various nuclear receptors by KSHV in BECs</p>

<p>PDF file - 491K, Supplemental Figure 1. Absence of RGS4 expression in KS tumor cells. Supplemental Figure 2. Blood vessel-specific expression of RGS4. Supplemental Figure 3. Morphometric vascular analyses of control and RGS4-expressing tumors of similar sizes that were harvested at various time points from NSG mice. Supplemental Figure 4. Expression of blood- and lymphatic-signature genes in SVECs and derivative cells.</p>

<p>PDF file - 491K, Supplemental Figure 1. Absence of RGS4 expression in KS tumor cells. Supplemental Figure 2. Blood vessel-specific expression of RGS4. Supplemental Figure 3. Morphometric vascular analyses of control and RGS4-expressing tumors of similar sizes that were harvested at various time points from NSG mice. Supplemental Figure 4. Expression of blood- and lymphatic-signature genes in SVECs and derivative cells.</p>