STAT3 is a major mediator of tumorigenesis, and has been shown to be vital for tumor cell growth, proliferation, and apoptosis [10–12]. Constitutive activation of STAT3 has been documented in ovarian, breast, colon, prostate, and several other types of cancer [5, 13–16]. Although the contribution of STAT3 to epithelial cancers and hematologic malignancies has been described in detail, little is known on the role of STAT3 dysregulation in sarcomas. The purpose of this study was to investigate the expression levels of STAT3 and pSTAT3 in various soft tissue tumors and to associate it with its clinicopathological characteristics. Our data suggests that STAT3 may be a key regulatory molecule in the malignant potential of soft tissue tumors and can be piloted as diagnostic marker in soft tissue tumors.
In the current study we observed a distinct pattern of STAT3 and pSTAT3 expression in soft tissue tumors, which differed significantly between benign, intermediate and malignant tumors and showed significant association with various histopathological parameters. Age group is not associated with STAT3 (P = 0.58) and pSTAT3 (P = 0.321) expressions. However, STAT3 and pSTAT3 expressions were significantly associated with grade of the tumor (P < 0.001). 46 out of the 48 malignant tumors (95.8%) and 6 out of the 9 intermediate tumors (66.7%) were STAT3 positive. Malignant tumors were 107.3 times more likely to express STAT3, when benign or intermediate tumor is the reference (OR = 107.3, 95% CI: 20.24-569). 24 out of the 48 malignant tumors (50%) and 4 out of the 9 intermediate tumors (44.4%) were pSTAT3 positive. Malignant tumors were 7.5 times more likely to express pSTAT3, when benign or intermediate tumor is the reference (OR = 7.5, 95% CI: 2.28-24.5). This is in agreement with the study by Chun et al, were it was observed that STAT3 signaling pathway is constitutively activated in rhabdomyosarcoma and osteosarcoma cells. It has been previously reported that STAT3 is overexpressed in cutaneous angiosarcoma, pyogenic granuloma, Ewing's sarcoma, Kaposi's sarcoma and in primary effusion lymphomas [18–20].
The other histopathological factors associated with STAT3 and pSTAT3 expressions were tumor location (P = 0.025, P = 0.027), plane of the tumor (P = 0.011, P = 0.006) and tumor necrosis (P = 0.001, P = 0.002). Out of 35 tumors in the lower extremities, 27(74.1%) were STAT3 positive and 15(42.9%) were pSTAT3 positive. 12 out of the 14 tumors in the retroperitoneum (85.7%) were STAT3 positive while pSTAT3 positives were 8(57.1%). Tumors in the retroperitoneum were more expressive of STAT3 (OR = 9.6, 95% CI: 1.48-62.15) and pSTAT3 (OR = 16, 95% CI: 1.6-159.3) when upper extremity is the reference. Tumor plane exhibited a positive trend with expression of STAT3 and pSTAT3, which were expressed in 51.16% and 18.6% of subcuitis, followed by the muscular plane (78.3% and 47.8%)) and body cavity (87.5% and 56.3%). Odds ratio for the muscular plane is 4.14 (95% CI 1.3-13.2) and body cavity is 8.05(1.62-39.8) for STAT3 expression. Odds ratio for muscular plane is 4.01(1.31-12.32) and body cavity is 5.6(1.6-19.6) for pSTAT3 when subcuitis as the reference. Out of the 21 tumors, which showed necrosis, 20 were found to be STAT3 positive (95.24%) and 13 were found to be pSTAT3 positive (61.9%). Tumors with necrosis were 18.13 times more likely to express STAT3 (OR = 18.13, 95% CI: 2.28-143.6) and 4.98 times more likely to express pSTAT3 (OR = 4.98, 95% CI: 1.7-14.3), when non-necrotic tumors are the reference.
In addition, tumor size also exhibited significant association with STAT3 expression (P = 0.003). Tumors greater than 10 cm and less than or equal to 15 cm in size were 19.38 times more likely to express STAT3 when tumors less than 5 cm is the reference (OR = 19.38, 95% CI: 2.25-166.5). We observed that tumors greater than 15 cm in size were 4.57 times more likely to express pSTAT3 when tumors less than 5 cm is the reference (OR = 4.57, 95% CI: 1.18-17.68). Significant association was observed between STAT3 expression and tumor circumscription (P = 0.001). Out of the 44 poorly circumscribed tumors 35 were STAT3 positive (79.55%). But pSTAT3 expression is not associated with tumor circumscription (P = 0.991). STAT3 and pSTAT3 expressions were not determined to associate with tumor capsulation (P = 0.21). However, whether STAT3 and pSTAT3 expression correlate with metastasis and recurrence needs to be evaluated.
The present study thus suggests that overexpression of STAT3 at the protein and gene level may be considered as a hallmark of sarcomas. Our data also indicates that increased activation of STAT3 could be associated with more aggressive biological behavior of soft tissue tumors. Although constitutive activation of STAT proteins is not the only contributing factor to transformation and cancer progression, its crucial role is still under investigation in soft tissue tumors. The mechanisms responsible for aberrant STAT activation in sarcomas remain uncertain and need further exploration. Moreover, knowledge of the cross-interaction of STAT molecules with other critical cellular proteins involved in growth regulation and survival may better serve to explain carcinogenesis in sarcomas.