The trefoil peptide family encompasses a group of small proteins that appear to assume a distinctive secondary structure that leads to intrinsic resistance to protease digestion. Induction of these peptides has been associated with response to injury in the gastrointestinal tract and related organs.

Transforming growth factor alpha (TGF-alpha) is thought to be involved in liver regeneration, cellular proliferation, and hepatocarcinogenesis. We have looked at the relationship between TGF-alpha and it's receptor, and have attempted to relate the expression of TGF-alpha and it's receptor to the differentiation of hepatocellular carcinoma (HCC) on serial sections of HCC. We examined immunohistochemically the expression of the TGF-alpha and of epidermal growth factor receptor (EGFR) proteins in the same area of 53 nodules (4 cm in diameter) of HCC obtained from patients. Immnnoreactive proteins were visualized by using a biotin-streptoavidin system (LSAB Kit, Dako). TGF-alpha was strongly expressed in 29 of 53 (54.7%) nodules. Specimens strongly positive for TGF-alpha were found mainly in well-differentiated HCC, while specimens positive for EGFR were found mainly in poorly differentiated HCC (pcO.05). In the tissues that stained weakly positive for TGFalpha, the expression of EGFR differed significantly, according to the degree of HCC histologic differentiation (pc0.05). These results led us to speculate that the expression of TGF-alpha and EGFR might be re-

Autocrine and paracrine modulation of transforming growth factor expression was assessed in rat intestinal epithelial cell lines designated IEC-6 and IEC-17. Addition of the transforming growth factor a (TGFa) homologue epidermal growth factor (EGF) to media of subconfluent IEC-6 cells led to autocrine stimulation of TGFa expression as well as increased expression of the transforming growth factor jB (TGF,81). Increased expression of TGFa was maximal between 3 and 6 h after addition of EGF and subsequently declined coincident with increasing level of expression of TGFl, which achieved maximal levels 6 h after addition of EGF and was sustained for more than 12 h. Addition of TGFftj also led to autocrine induction of its own expression coincident with suppression of TGFa expression. Addition of TGFftj was associated with increased expression of f-actin when standardized to a constitutive transcript (GAPDH). Similar responses to addition of EGF and TGF,#I, were observed in another intestinal epithelial cell line, designated IEC-17. Modulation of expression of TGFs was attenuated when cells were grown on the complex extracellular matrix produced by the Engelbreth-Holm-Swarm tumor (Matrigel), reflecting the baseline induction of TGF,81 expression when compared to IEC-6 and IEC-17 cells maintained on plastic. These observations suggest that expression of TGFs is controlled by autocrine mechanisms in intestinal epithelial cell lines and proliferation stimulated by TGFa may be initially self-reinforcing but ultimately downregulated by induction of TGFj#I. (J. Clin. Invest. 1991. 87:2216-2221

Background. A precise prognostic factor for small hepatocellular carcinoma (HCC), the diagnosis of which recently has increased in incidence because of the development of diagnostic imaging techniques, is desirable. It has been reported that proliferating cell nuclear antigen (PCNA) would be related to proliferating cells, and thus the PCNA labeling index may provide useful information about the biologic behavior of small HCC. Methods. An assessment was made of proliferative activity by immunohistochemical staining using a monoclonal antibody against PCNA in 46 nodules of HCC less than 3 cm in diameter resected from 44 patients. A correlation between PCNA labeling index and clinicopathologic findings or prognosis was sought. Results. The mean labeling index was 18.7% in HCC and 1.9% in nontumor liver tissue. The labeling index corresponded to the degree of histologic differentiation, and the labeling index of well differentiated HCC was significantly lower (P < 0.05) than that of moderately or poorly differentiated HCC. The incidence of capsule formation in the high labeling index group (labeling index ± 20%) was significantly higher (P < 0.05) than that in the low labeling index group (labeling index < 20%). A high incidence of capsular and vascular invasion was found in the high labeling index group. The survival rate after resection was significantly higher (P < 0.05) and the recurrence rate significantly lower (P < 0.05) in the low labeling index group than in the high labeling index group. Conclusions. The PCNA labeling index was shown to be closely related to histologic characteristics, and proved to be a useful indicator of recurrence and survival in small HCC.