Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

LIN28 expression and prognostic value in hepatocellular carcinoma patients who meet the Milan criteria and undergo hepatectomy

Stem cell marker LIN28,related closely with SOX2 and OCT4,has been studied as a biomarker for the maintainance of pluripotent cells in several malignancies.Our previous study showed that SOX2 and OCT4 were negative predictors for hepatocellular carcinoma(HCC).However,the predictive value of LIN28 in HCC outcome is still undetermined.We hypothesized that LIN28 may also play a role as a biomarker for HCC.To test this hypothesis,we examined the expression of LIN28 in 129 radically resected HCC tissues using reverse transcription-polymerase chain reaction and analyzed the association of LIN28 expression with clinicopathologic features and prognosis.Our study showed that LIN28 was expressed at a higher frequency in tumor tissues than in non-HCC tissues(45.0% vs.21.7%,P = 0.020).Moreover,LIN28 expression was significantly increased in cases with large tumor size(P = 0.010).Univariate analysis did not reveal a significant correlation between LIN28 expression and overall survival or recurrence-free survival.For HCC patients who met the Milan criteria,stratified analysis revealed shorter overall survival(P = 0.007) and recurrence-free survival(P < 0.001) in those with detectable LIN28 expression compared to those with no detectable LIN28 expression.Furthermore,multivariate analysis revealed that LIN28 was a negative independent predictor for both overall survival(hazard ratio= 7.093,P = 0.017) and recurrence-free survival(hazard ratio=5.518,P = 0.004) in patients who met the Milan criteria.Taken together,our results suggest that LIN28 identifies low-risk and high-risk subsets of HCC patients meeting the Milan criteria who undergo hepatectomy.

Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma(HCC).Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown.Here,we identified an oncogenic lncRNA that was upregulated in HCC and was transcriptionally induced by TGF-β(named lnc-UTGF,lncRNA upregulated by TGF-β).Upon TGF-βstimulation,SMAD2/3 bound to the lnc-UTGF promoter and activated lnc-UTGF expression.In turn,the TGF-β/SMAD signaling was augmented by overexpressing lnc-UTGF,but was inhibited by silencing lnc-UTGF.Mechanism investigations revealed that lnc-UTGF interacted with the mRNAs of SMAD2 and SMAD4 via complementary base-pairing,resulting in enhanced stability of SMAD2/4 mRNAs.These data suggest a novel TGF-β/SMAD/lnc-UTGF positive feedback circuitry.Subsequent gain-and loss-of-function analyses disclosed that lnc-UTGF promoted the migration and invasion of hepatoma cells,and this effect of lnc-UTGF was attenuated by repressing SMAD2/4 expression or by mutating the SMAD2/4-binding sites in lnc-UTGF.Studies using mouse models further confirmed that in vivo metastasis of hepatoma xenografts was inhibited by silencing lnc-UTGF,but was enhanced by ectopic expression of lncUTGF.The lnc-UTGF level was positively correlated with the SMAD2/4 levels in xenografts.Consistently,we detected an association of lnc-UTGF upregulation with increase of SMAD2,SMAD4,and their metastasis effector SNAIL1 in human HCC.And high lnc-UTGF level was also significantly associated with enhanced metastasis potential,advanced TNM stages,and worse recurrence-free survival.Conclusion:there exists a lnc-UTGF-mediated positive feedback loop of the TGF-βsignaling and its deregulation promotes hepatoma metastasis.These findings may provide a new therapeutic target for HCC metastasis.

Correction: Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00781-3,published online 17 November 2021 In this article^(1) Jian-Hong Fang should have been denoted as a corresponding author along with Shi-Mei Zhuang,but was inadvertently removed during the production process.The original article has been corrected.