p28^GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity

It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma （HCC）, plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum （ER） stress. During ER stress, p28GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell＇s ability to cope with the stress conditions. Furthermore, p28GANK upregulates glucose-regulated protein 78 （GRP78）, a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B （NF-κB） activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28GANK has potential implications for HCC progression under the ER stress conditions.

Postoperative adjuvant transcatheter arterial chemoembolization improves the prognosis of patients with huge hepatocellular carcinoma

Background: Surgical resection of huge hepatocellular carcinoma(HCC, ≥ 10 cm) is potentially curative. More adjuvant treatments are needed to reduce relapses in these patients. We evaluated the influence of postoperative adjuvant transcatheter arterial chemoembolization(PA-TACE) on the prognosis of huge HCC. Methods: Data from consecutive patients who underwent curative resection for huge HCC in our center were retrospectively collected. Recurrence-free survival(RFS) and overall survival(OS) were compared between patients who did and did not undergo PA-TACE. Propensity score matching(PSM) was used. Results: Among the 255 enrolled patients, 93 underwent PA-TACE. The clinical outcomes were significantly better in the PA-TACE group than those in the non PA-TACE group(5-year RFS rate: 33.5% vs. 18.0%;5-year OS rate: 47.0% vs. 28.0%, all P<0.001). After PSM, similar results were obtained(5-year RFS rate: 28.8% vs. 17.6%, P<0.001;5-year OS rate: 42.5% vs. 25.0%, P=0.004). PA-TACE decreased the possibility of early recurrence(<2 years, crude cohort: P<0.001, PSM cohort: P<0.001) but not late recurrence( ≥ 2 years, crude cohort: P=0.692, PSM cohort: P=0.325). Multivariable Cox regression analysis suggested that PA-TACE was an independent protective factor prolonging early RFS, RFS and OS. Conclusions: PA-TACE is a safe intervention for huge HCC patients after liver resection and improves outcomes.

Pathologic assessment of hepatocellular carcinoma in the era of immunotherapy:a narrative review

Background and Objective:Immune checkpoint inhibitor(ICI)-based therapy has achieved impressive success in various cancer types.Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma(HCC)in recent decade.Meanwhile,numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival,respectively.In this review,we aim to summarize some pragmatic histomorphologic,immunohistochemical,and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC.Methods:We searched PubMed using the terms hepatocellular carcinoma,immunotherapy,immune checkpoint inhibitor,immune checkpoint blockade,conversion therapy,neoadjuvant therapy,adjuvant therapy,biomarker,pathologic evaluation,pathologic assessment till February 2023.Key Content and Findings:Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens,it is encouraging that a few of studies have concentrated on this field,and moreover,the methods and parameters noted on other cancer types are also worthy of reference.For the pathologic assessment of HCC specimens underwent immunotherapy,a suitable sampling scheme,identifying immunotherapy-related pathologic response,and quantification of pathologic response rate should be emphasized.For the patients of HCC who are scheduled to receive immunotherapy,tumor-infiltrating lymphocyte,intratumoral tertiary lymphoid structure,programmed cell death ligand 1,Wnt/β-catenin,microsatellite instability and mismatch repair,tumor mutational burden and tumor neoantigen,as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI.Conclusions:The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report.Albeit many related researches are preclinical or insufficient,they may tremendously alter the immunotherapy strategy of HCC in future.