LANA-1, Bcl-2, Mcl-1 and HIF-1α protein expression in HIV-associated Kaposi sarcoma

Abstract

Human herpesvirus 8 (HHV8) is necessary for Kaposi sarcoma (KS) to develop, but whether the tissue viral load is a marker of KS progression is still unclear. Little is known about the level of expression of apoptosis-regulating proteins and of hypoxia-inducible factors (HIFs) in KS tumour cells relative to HHV8 expression. We therefore investigated the expression of the latency-associated nuclear antigen (LANA-1) of HHV8, Bcl-2, Mcl-1, Bax, Bcl-xL, caspase 3 and HIF-1alphain KS tissue specimens at different stages of the disease. The expression of these proteins was evaluated immunohistochemically using tissue microarrays (TMAs) in tissue specimens from 245 HIV-positive patients at different stages of the disease. Both LANA-1 and HIF-1alpha were expressed in KS biopsies taken at different stages, but their level increased throughout tumour progression. Additionally, the levels of Bcl-2 and Mcl-1 were higher in visceral KS lesions compared to levels observed in cutaneous and mucosal KS. This study demonstrates that late tumour stages of KS in tissues from HIV-positive patients are associated with high levels of LANA-1, HIF-1alpha and of the anti-apoptotic proteins, Bcl-2 and Mcl-1. Finally, the expression of these proteins can be potentially used as a tissue biomarker in defining patients with a higher risk of disease progression.

Biomarkers of HIV-associated Cancer

“…Early-stage KS represents a reactive lesion that can either regress or progress. Progression is related to the long-lasting expression of HHV8 latency genes in KS lesions, including latent nuclear antigen-1 (LANA-1),21 cyclin-D1,27,28 and bcl-2 29. HHV8-related induction of the receptor tyrosine kinase c-kit was shown by gene expression profiling in cultured endothelial cells to play a key role in KS tumorigenesis 30,31…”

“…LANA-1 protein may cause dysfunction of cell cycle regulatory checkpoints by degrading p53 and inactivating pRb 37. It has been previously shown that positive immunostaining for HHV8 LANA-1 exhibits high sensitivity and specificity, and it is a reliable and cost-effective method for the diagnosis of KS and is also useful for distinguishing it from the mimickers 21,25,29…”

Molecular Biology of Kaposi's Sarcoma-associated Herpesvirus and Related Oncogenesis

“…Furthermore, both latent antigens LANA and vIRF3 play a role on the HIF1 α stabilization via protein–protein interaction (Cai et al , 2006b, 2007; Shin et al , 2008). Recent analysis of clinical patient samples further supported a role for LANA in stabilization of HIF1α (Long et al , 2009). Interestingly, the lytic antigen vGPCR has also been shown to upregulate VEGF expression through activation of HIF1α expression (Sodhi et al , 2000).…”

Reversal effect of vitamin D on different multidrug-resistant cells

“…Ex vitro and animal experiments have shown that vitamin D can induce mouse myeloid leukemia cell differentiation and prolong the survival time of leukemia mice. Additional studies (Seo et al, 2005;Long et al, 2009) Recent studies have found that ATRA and vitamin D can significantly improve the sensitivity of multidrug resistance of tumor cells to chemotherapy drugs. Studies have also confirmed that ATRA and vitamin D, combined with chemotherapy, have a synergistic effect on the enhancement of lung cancer susceptibility.…”