Tim-3 Expression in Cervical Cancer Promotes Tumor Metastasis

Abstract

BackgroundT cell immunoglobulin mucin-3 (Tim-3) has been identified as a negative regulator of anti-tumor immunity. Recent studies highlight the important role of Tim-3 in the CD8+ T cell exhaustion that takes place in both human and animal cancer models. However, the nature of Tim-3 expression in the tumor cell and the mechanism by which it inhibits anti-tumor immunity are unclear. This present study aims to determine Tim-3 is expressed in cervical cancer cells and to evaluate the role of Tim-3 in cervical cancer progression.MethodologyA total of 85 cervical tissue specimens including 43 human cervical cancer, 22 cervical intraepithelial neoplasia (CIN) and 20 chronic cervicitis were involved. Tim-3 expression in tumor cells was detected and was found to correlate with clinicopathological parameters. Meanwhile, expression of Tim-3 was assessed by RT-PCR, Western Blot and confocal microscopy in cervical cancer cell lines, HeLa and SiHa. The migration and invasion potential of Hela cells was evaluated after inhibiting Tim-3 expression by ADV-antisense Tim-3.ConclusionsWe found that Tim-3 was expressed at a higher level in the clinical cervical cancer cells compared to the CIN and chronic cervicitis controls. We supported this finding by confirming the presence of Tim-3 mRNA and protein in the cervical cell lines. Tim-3 expression in tumor cells correlated with clinicopathological parameters. Patients with high expression of Tim-3 had a significant metastatic potential, advanced cancer grades and shorter overall survival than those with lower expression. Multivariate analysis showed that Tim-3 expression was an independent factor for predicting the prognosis of cervical cancer. Significantly, down-regulating the expression of Tim-3 protein inhibited migration and invasion of Hela cells. Our study suggests that the expression of Tim-3 in tumor cells may be an independent prognostic factor for patients with cervical cancer. Moreover, Tim-3 expression may promote metastatic potential in cervical cancers.

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells

“…Recent studies reported the ectopic expression of TIM-3 in lineages other than hematopoietic cells, particularly in primary cancer cells, including melanoma [52], non-small cell lung cancer [53], cervical cancer [54] and liposarcoma [55]. Importantly, patients with TIM-3 positive cancer cells had a significantly shorter survival time than those with TIM-3 negative cancer cells in non-small cell lung cancer [53] and cervical cancer [54].…”

“…Importantly, patients with TIM-3 positive cancer cells had a significantly shorter survival time than those with TIM-3 negative cancer cells in non-small cell lung cancer [53] and cervical cancer [54]. TIM-3 expression in these various types of malignant cells raises the possibility of tumorigenic function of TIM-3.…”

Tim-3 and Tim-4 as the potential targets for antitumor therapy

“…Jajosky et al also pointed out that, RepSox (a reprogramming tool and inhibitor of transforming growth factor-b receptor 1) accelerated loss of Tim-3 from the surface of AML cells by inhibiting TGF-b signaling. 34 Tim-3 as human cancer prognostic factor The expression of TIM-3 on T cells was poor clinic pathological parameters such as nodal metastasis and advanced cancer stages in gastric cancer, 35 lung cancer, 36 cervical cancer 37 and ovarian cancer. 38 The ectopic expression of TIM-3 in tumor cells has been suggested as a potential, independent prognostic factor for patients with lung cancer, 36 cervical cancer 37 and prostate cancer.…”

“…34 Tim-3 as human cancer prognostic factor The expression of TIM-3 on T cells was poor clinic pathological parameters such as nodal metastasis and advanced cancer stages in gastric cancer, 35 lung cancer, 36 cervical cancer 37 and ovarian cancer. 38 The ectopic expression of TIM-3 in tumor cells has been suggested as a potential, independent prognostic factor for patients with lung cancer, 36 cervical cancer 37 and prostate cancer. 39 The Tim-3/galectin-9 signaling pathway mediates Tcell senescence was also involved in patients with hepatitis B virus (HBV)-associated HCC, thus it has been a potential immunotherapeutic target.…”

Emerging immune checkpoints for cancer therapy

“…TiM-3 belongs to the TiM family and was initially observed selectively expressed on terminally differentiated interferon g-producing CD4  T helper type 1 (Th1) cells and CD8  cytotoxic T cells [64,65], as well as on Th17, DCs, monocytes, Tregs, mast cells, nK cells, TiLs, also on tumor cells, such as melanoma, SCC, gastric cancer and nSCLC cells, but indeed not on CD4  T helper type 1 (Th2) cells [65][66][67][68][69][70][71][72][73].…”