Effects of retinoic acid combined with interferon-gamma on the expression of a tumor rejection antigen (heat shock protein gp96) in human cervical cancer

Abstract

Santin AD, Hermonat PL, Ravaggi A, Chiriva‐Internati M, Pecorelli S, Parham GP. Effects of retinoic acid combined with interferon‐γ on the expression of a tumor rejection antigen (heat shock protein gp96) in human cervical cancer. Int J Gynecol Cancer 1998; 8: 158–163. Retinoids and interferons are important regulators of human epithelial cell differentiation and have been used successfully in the clinical treatment of HPV‐involved cervical cancer. Hsp‐gp96 molecules recently have been implicated in the presentation pathways of tumor and viral antigens and have resulted in an effective protein vaccine in several tumor animal models. In this study, we analyzed at the transcriptional (northern blot) and post‐transcriptional levels (western blot) the effects of retinoic acid and interferon‐γ alone or in combination on the expression of the tumor rejection antigen heat shock protein‐gp96 molecules (Hsp‐gp96) in two human cervical carcinoma cell lines (SiHa and HT‐3). Exposure to retinoic acid or IFN‐γ was able to upregulate the expression of Hsp‐gp96 molecules in both cervical cell lines studied. Exposure to the combination of IFN‐γ plus retinoic acid significantly upregulated (in an additive manner) Hsp‐gp96 molecules when compared to the levels obtained after exposure to IFN‐γ or retinoic acid alone. Northern blot analysis of mRNA for Hsp‐gp96 molecule confirmed that the activity of both of these biologic response modifiers was at the transcriptional level. Taken together, these data indicate that the combination of these modalities could induce a previously unrecognized additive effect on the expression of another immunologically important antigen, the Hsp‐gp96 tumor rejection antigen, in human cervical cancer cells. These findings extend previous reports on the effects of retinoids and IFN‐γ on tumor cells and provide further support for the combined use of these powerful biologic response modifiers in the adjuvant treatment of cervical cancer.

Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

“…The role of gp96 in HCC tumorigenicity is not clear, but some studies have suggested that high-level expression of gp96 could contribute to tumerigenicity of other tumours [23,32,33] . Gp96 expression was also reported to increase the immunity to tumours [34][35][36][37][38] . At least the complex preparation of gp96 and bound-peptides has been being successfully used as autologous tumour vaccines [13][14][15][16] .…”

Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

“…The role of gp96 in HCC tumorigenicity is not clear, but some studies have suggested that high-level expression of gp96 could contribute to tumerigenicity of other tumours [23,32,33] . Gp96 expression was also reported to increase the immunity to tumours [34][35][36][37][38] . At least the complex preparation of gp96 and bound-peptides has been being successfully used as autologous tumour vaccines [13][14][15][16] .…”

Overexpression of glucose-regulated protein 94 (Grp94) in esophageal adenocarcinomas of a rat surgical model and humans

“…In rat colon adenocarcinoma cell lines more tumorigenic clones expressed more Grp94 under normal and stressed conditions (25). Grp94 transcription is generally activated by various stresses (26), such as treatment with lipopolysaccharide, phorbol esters, inflammatory mediators (24,27), irradiation (28) and chemotherapeutic agents (29,30), as well as conditions of hypoxia, acidosis, glucose deprivation and low nutrient supply (31). The rat EGDA model is a chronic inflammation-driven carcinogenesis model.…”

Expression of Stress-Response and Cell Proliferation Genes in Renal Cell Carcinoma Induced by Oxidative Stress

“…For example, irradiation and interleukin-6 administration induced gp96 in human cervical and breast cancers, respectively. 33,34 These two proteins are coexistent with a broad range of antigen peptides derived from that particular cell and are named as tumor rejection antigen for gp 96 35 or tumor-specific transplantation antigen for HSP86, 36 and autologous tumor-derived gp96 was used successfully for immunotherapy of tumors. 35 HSP86 has been constitutively induced in murine embryonal carcinoma, but is decreased on differentiation, 37 suggesting induction of these proteins as a common molecular event in cancers.…”

Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

“…The role of gp96 in HCC tumorigenicity is not clear, but some studies have suggested that high-level expression of gp96 could contribute to tumerigenicity of other tumours [23,32,33] . Gp96 expression was also reported to increase the immunity to tumours [34][35][36][37][38] . At least the complex preparation of gp96 and bound-peptides has been being successfully used as autologous tumour vaccines [13][14][15][16] .…”

Overexpression of glucose-regulated protein 94 (Grp94) in esophageal adenocarcinomas of a rat surgical model and humans

“…In rat colon adenocarcinoma cell lines more tumorigenic clones expressed more Grp94 under normal and stressed conditions (25). Grp94 transcription is generally activated by various stresses (26), such as treatment with lipopolysaccharide, phorbol esters, inflammatory mediators (24,27), irradiation (28) and chemotherapeutic agents (29,30), as well as conditions of hypoxia, acidosis, glucose deprivation and low nutrient supply (31). The rat EGDA model is a chronic inflammation-driven carcinogenesis model.…”

Expression of Stress-Response and Cell Proliferation Genes in Renal Cell Carcinoma Induced by Oxidative Stress

“…For example, irradiation and interleukin-6 administration induced gp96 in human cervical and breast cancers, respectively. 33,34 These two proteins are coexistent with a broad range of antigen peptides derived from that particular cell and are named as tumor rejection antigen for gp 96 35 or tumor-specific transplantation antigen for HSP86, 36 and autologous tumor-derived gp96 was used successfully for immunotherapy of tumors. 35 HSP86 has been constitutively induced in murine embryonal carcinoma, but is decreased on differentiation, 37 suggesting induction of these proteins as a common molecular event in cancers.…”

Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

“…The role of gp96 in HCC tumorigenicity is not clear, but some studies have suggested that high-level expression of gp96 could contribute to tumerigenicity of other tumours [23,32,33] . Gp96 expression was also reported to increase the immunity to tumours [34][35][36][37][38] . At least the complex preparation of gp96 and bound-peptides has been being successfully used as autologous tumour vaccines [13][14][15][16] .…”

Overexpression of glucose-regulated protein 94 (Grp94) in esophageal adenocarcinomas of a rat surgical model and humans

“…In rat colon adenocarcinoma cell lines more tumorigenic clones expressed more Grp94 under normal and stressed conditions (25). Grp94 transcription is generally activated by various stresses (26), such as treatment with lipopolysaccharide, phorbol esters, inflammatory mediators (24,27), irradiation (28) and chemotherapeutic agents (29,30), as well as conditions of hypoxia, acidosis, glucose deprivation and low nutrient supply (31). The rat EGDA model is a chronic inflammation-driven carcinogenesis model.…”

Expression of Stress-Response and Cell Proliferation Genes in Renal Cell Carcinoma Induced by Oxidative Stress

“…For example, irradiation and interleukin-6 administration induced gp96 in human cervical and breast cancers, respectively. 33,34 These two proteins are coexistent with a broad range of antigen peptides derived from that particular cell and are named as tumor rejection antigen for gp 96 35 or tumor-specific transplantation antigen for HSP86, 36 and autologous tumor-derived gp96 was used successfully for immunotherapy of tumors. 35 HSP86 has been constitutively induced in murine embryonal carcinoma, but is decreased on differentiation, 37 suggesting induction of these proteins as a common molecular event in cancers.…”