We conducted this study to examine the prognostic significance of p-STAT3 expression in a large cohort of colorectal cancers. STAT3 is aberrantly activated in a wide variety of human cancers and plays crucial roles in tumor cell proliferation, survival, invasion and tumor-promoting inflammation (1
). Given the potential for STAT3 as an anti-cancer therapeutic target (9
), a better understanding of STAT3 activation in human cancer tissues is important. Nonetheless, prognostic studies on p-STAT3 expression in colorectal cancer have been inconclusive. We have found that p-STAT3 expression is significantly associated with poor prognosis in a database of 724 colorectal cancers, suggesting a potential role of p-STAT3 expression as a prognostic biomarker in colorectal cancer.
Examining biomarkers or prognostic factors is important in cancer research (42
). Studies examining the relation between p-STAT3 expression and prognosis in colorectal cancer have yielded inconsistent results (16
) (); p-STAT3 expression was associated with poor prognosis in two studies [N=90 (16
) and N=108 (17
)], whereas one study [N=104 (19
)] showed good prognosis associated with p-STAT3 expression, and another study [N=126 (18
)] showed no prognostic value of p-STAT3. All of these previous studies were limited by small sample sizes and low statistical power (). Importance of large-scale studies cannot be emphasized enough, because small studies (for example, N<150) with null results have much higher likelihood of being unpublished than small studies with “significant” results, leading to publication bias. In contrast to the prior small studies (16
), our study examined p-STAT3 expression in a much larger cohort of stage I-IV colorectal cancers. Nonetheless, our finding on the relationship between p-STAT3 expression and poor prognosis in colorectal cancer needs to be confirmed by independent datasets in the future.
Studies on phosphorylated STAT3 (p-STAT3) expression and colorectal cancer patient survival
Experimental studies using colon cancer cell lines have suggested an oncogenic role of STAT3. Inhibition of STAT3 with small interfering RNA has induced apoptosis and cell cycle arrest in colon cancer cells (22
). STAT3 activation triggered through interleukin-6 and through a constitutively active STAT3
mutant has enhanced cell proliferation and tumor growth (21
). STAT3 activation has been shown to promote tumor growth through the induction of matrix metalloproteinase (20
). A small study (N=90) has shown a positive association between p-STAT3 expression and nuclear accumulation of CTNNB1 (16
). In our current study, however, we did not find significant association between p-STAT3 expression and CTNNB1 status. This discrepancy might be caused by differences in immunohistochemical methods, correlative errors, or study samples, or simply due to a chance variation in the small underpowered study. In addition, STAT3 signaling has been implicated in TFF3 and VEGFA-mediated invasion and growth of colon cancer cells (23
). Our observational data certainly support a role of STAT3 in colorectal cancer progression.
Interestingly, we have found the relationship of p-STAT3 expression with peritumoral lymphocytic reaction and intratumoral periglandular reaction, independent of the clinical and molecular variables that we examined. STAT3 has been implicated in tumor-promoting inflammation and the regulation of host immune response in the tumor microenvironment (1
). Our current data certainly support a potential role of STAT3 in the propagation of tumor-promoting inflammation. Because of the relationship between MSI and lymphocytic reactions as well as the fundamental importance of MSI in governing the phenotype of colorectal cancer, we examined the relationship between p-STAT3 and MSI as well as a potential interaction between p-STAT3 and MSI in survival analysis. However, we did not observe a significant association between p-STAT3 and MSI-high, or a significant interaction between p-STAT3 and MSI. Future studies are necessary to elucidate biological mechanisms by which tumor STAT3 activation influences lymphocytic reaction in the tumor microenvironment.
There are limitations in this study. For example, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use substantially differed according to STAT3 status in tumor, since such data were unavailable for treatment decision making. In addition, our multivariate survival analysis finely adjusted for disease stage (I, IIA, IIB, IIIA, IIIB, IIIC, IV, unknown), on which treatment decision making was mostly based. As another limitation, beyond cause of mortality, data on cancer recurrences were unavailable in these cohort studies. Nonetheless, with a median follow-up of greater than 10 years for censored cases, colorectal cancer-specific mortality was a reasonable colorectal cancer-specific outcome.
There are advantages in utilizing the database of the two prospective cohort studies. Data on family history, cancer staging, and other clinical, pathologic, and tumoral molecular variables were prospectively collected, blinded to patient outcome. Cohort participants who developed cancer were treated at hospitals throughout the U.S., in 48 States except for North Dakota and Alaska, and thus more representative colorectal cancer cases in the general U.S. population than patients in one to a few academic hospitals. In addition, we assessed the effect of p-STAT3 expression independent of other critical molecular events [e.g., BRAF
LINE-1 hypomethylation, and microsatellite instability (MSI)] or pathologic features (e.g., lymphocytic reaction) that have been documented to be associated with colorectal cancer prognosis (26
In summary, our large study has shown that individuals with STAT3-activated colorectal cancers experience a poorer prognosis, supporting a tumor-promoting role of STAT3. Considering that drugs targeting the STAT3 pathway are intensively being developed and tested in clinical trials for various human cancers (9
), p-STAT3 expression in colorectal cancer might serve as a predictive tissue biomarker and can be used for patient selection in clinical trials of these drugs. In this respect, our findings may have substantial clinical implications.
Statement of Translational Relevance
STAT3 is constitutively activated in a variety of human cancers including colorectal cancer and plays crucial roles in cancer cell proliferation, survival and metastasis. Accumulating evidence has implicated STAT3 as a promising target for cancer therapy and chemoprevention. However, the relation between p-STAT3 expression (i.e., STAT3 activation) in colorectal cancer and patient survival has been controversial. We have utilized the database of more than 700 colorectal cancers in two independent, prospective cohort studies, with available clinical information, adequate follow-up, and other important molecular events in colorectal cancers. To our knowledge, this is the first large study to demonstrate influence of p-STAT3 expression on adverse clinical outcome independent of clinical, pathologic and molecular features of colorectal cancer. Thus, our findings are relevant to practice in oncology.