A prognostic insight on in vivo expression of interleukin-6 in uterine cervical cancer

Srivani, R; Nagarajan, B.

doi:10.1046/j.1525-1438.2003.13197.x

Cited by 52 publications

(33 citation statements)

References 22 publications

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“…Of note, we and other groups have previously shown that IL-6 and M-CSF are highly upregulated in human cervical carcinogenesis in situ (26,27). IL-6 has been correlated with a negative prognosis in these patients (36). Cervical cancer cells hardly responded to IL-6, and this suggested a paracrine role for IL-6 (27).…”

Section: Discussionmentioning

confidence: 61%

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

et al. 2011

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In many tumors, the switch from precancerous lesions to malignancy critically relies on expression of the matrix-metalloprotease MMP-9, which is predominantly provided by infiltrating inflammatory cells. Our study defines a novel molecular cascade, how human neoplastic cells instruct tumor-associated myeloid cells to produce MMP-9. In biopsies of human papillomavirus-associated precancerous cervical intraepithelial neoplasia (CIN III lesions), we show broad activation of the transcription factor STAT3 and coexpression of MMP-9 in perivascular inflammatory cells. For the first time, we establish a causative link between tumor-mediated paracrine STAT3 activation and MMP-9 production by human tumor-instructed monocytes, whereas NF-kB activation is dispensable for this response. Our data provide evidence that STAT3 does not directly induce MMP-9 but first leads to a strong production of the monocyte chemoattractant protein-1 (CCL2) in the nanogram range. In a second phase, autocrine stimulation of the CCR2 receptor in the tumor-instructed monocytes amplifies MMP-9 expression via intracellular Ca 2þ signaling. These findings elucidate a critical mechanism in the molecular pathobiology of cervical carcinogenesis at the switch to malignancy. Particularly in tumors, which are associated with infectious agents, STAT3-driven inflammation may be pivotal to promote carcinogenesis, while at the same time limit NF-kB-dependent immune responses and thus rejection of the infected preneoplastic cells. The molecular cascade defined in this study provides the basis for a rational design of future adjuvant therapies of cervical precancerous lesions.

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Section: Discussionmentioning

confidence: 61%

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

et al. 2011

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“…It is well-known that host immune response and chronic inflammation play critical roles on preventing the progression of cervical cancer (Shi et al, 2013). IL-6, an important pro-inflammatory cytokine, is a multifunctional protein principally involved in the genesis and maintenance of the inflammatory response (Kyo et al, 2000;Srivani et al, 2003;Shi et al, 2013). There is local production of IL-6 in cervicovaginal secretions.…”

Section: Discussionmentioning

confidence: 99%

Stratification Analysis and Case-control Study of Relationships between Interleukin-6 Gene Polymorphisms and Cervical Cancer Risk in a Chinese Population

Shi¹,

Líu²,

Wu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…IL6 has a negative impact on the prognosis of a patient (16). We have shown that it mainly acts in a paracrine manner and creates a protumorigenic and immunosuppressive microenvironment (10,17,18).…”

Section: Introductionmentioning

confidence: 93%

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

et al. 2016

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Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from lowgrade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo. Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872-83. Ó2016 AACR.

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A prognostic insight on in vivo expression of interleukin-6 in uterine cervical cancer

Cited by 52 publications

References 22 publications

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression

Stratification Analysis and Case-control Study of Relationships between Interleukin-6 Gene Polymorphisms and Cervical Cancer Risk in a Chinese Population

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

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