Abstract
Background and Objective: Hepatocyte nuclear factor 3β (HNF3β) is a key transcription factor in the development of the gastrointestinal tract. However, only few studies have examined its' expression, function and potential clinical significance in colorectal cancer tumorigenesis and progression.Methods: HNF3β expression in colorectal cancer tissue samples of 174 patients was assessed by immunohistochemistry. The results were analyzed with respect to patients' clinicopathological characteristics and survival. Following the in vitro cell transfection, MTT, wound healing, and Transwell assays were used to test cell proliferation, migration, and invasion, respectively. Western blot was used to examine IL6, JAK1, and STAT3 protein expression. The potential for tumor formation was evaluated using a mouse xenograft model.Results: HNF3β expression was lower in colon cancer tissue compared to normal tissue and correlated with UICC clinical stage (P = 0.001), depth of invasion (P = 0.004), regional lymph node metastasis (P = 0.007), distant metastasis (P = 0.048), and poor survival (P < 0.001) in patients with colorectal cancer. Furthermore, HNF3β overexpression impeded proliferation, migration and invasion of SW480 cells via JAK-STAT3 signaling in vitro. Moreso, HNF3β overexpression showed a significant growth inhibition of subcutaneous xenograft tumors in vivo.Conclusions: The results show that HNF3β acts as a suppressor of colorectal cancer progression and decreased HNF3 β expression is closely related to the poor prognosis. Thus, HNF3β may be a potential molecular target for inhibition of colorectal cancer cells and development of new anti-tumor therapies.
Highlights
Some progress has been made in the management of colorectal cancer based on early diagnosis, radical surgery, radiotherapy, and neoadjuvant chemotherapy, recurrence and metastases remain a major cancer management issue which has yet to be solved [1, 2]
The remaining tumor samples were positive for Hepatocyte nuclear factor 3β (HNF3β) protein staining, and 41.95% (73/174), 37.93% (66/174), and 5.75% (107/174) were categorized as weak (+), moderate (++), and strong (+++)
Weak or negative HNF3β protein expression was observed in 56.32% (98/174) of colon tumor samples (Figure 1Ae,f), while normal colorectal tissues examined in this study (6 samples) showed strong positive HNF3β staining (Figure 1Aa)
Summary
Some progress has been made in the management of colorectal cancer based on early diagnosis, radical surgery, radiotherapy, and neoadjuvant chemotherapy, recurrence and metastases remain a major cancer management issue which has yet to be solved [1, 2]. There is an urgent need to explore and define potential molecular biomarkers for early diagnosis, as HNF3β Suppresses Colorectal Cancer Progression well as tumor recurrence and metastasis. Hepatocyte nuclear factor 3β (HNF3β), is a key member of the hepatocyte nuclear factor (HNF) family with an important role in embryogenesis [3]. It has been shown that HNF3 transcription factors, especially HNF3α/FOXA1, HNF3β/FOXA2, and HNF3γ/FOXA3, are involved in the development and differentiation of the gastrointestinal tract [4]. Many studies have shown that HNF3β suppression is closely related to tumorigenesis, progression, and metastasis of several different types of cancer including hepatocellular carcinoma, lung cancer, pancreatic cancer, gastric cancer, and thyroid cancer [10,11,12,13,14]. Hepatocyte nuclear factor 3β (HNF3β) is a key transcription factor in the development of the gastrointestinal tract. Only few studies have examined its’ expression, function and potential clinical significance in colorectal cancer tumorigenesis and progression
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