Ginsenoside Rg3 decreases breast cancer stem-like phenotypes through impairing MYC mRNA stability.

Breast cancer stem cells (BCSCs) are responsible for breast cancer metastasis, recurrence and treatment resistance, all of which make BCSCs potential drivers of breast cancer aggression. Ginsenoside Rg3, a traditional Chinese herbal medicine, was reported to have multiple antitumor functions. Here, we revealed a novel effect of Rg3 on BCSCs. Rg3 inhibits breast cancer cell viability in a dose- and time-dependent manner. Importantly, Rg3 suppressed mammosphere formation, reduced the expression of stemness-related transcription factors, including c-Myc, Oct4, Sox2 and Lin28, and diminished ALDH(+) populations. Moreover, tumor-bearing mice treated with Rg3 exhibited robust delay of tumor growth and a decrease in tumor-initiating frequency. In addition, we found that Rg3 suppressed breast cancer stem-like properties mainly through inhibiting MYC expression. Mechanistically, Rg3 accelerated the degradation of MYC mRNA by enhancing the expression of the let-7 family, which was demonstrated to bind to the MYC 3' untranslated region (UTR). In conclusion, our findings reveal the remarkable suppressive effect of Rg3 on BCSCs, suggesting that Rg3 is a promising therapeutic treatment for breast cancer.

Lenvatinib as second-line treatment in patients with unresectable hepatocellular carcinoma: A retrospective analysis.

Objective: The purpose of this study is to determine the efficacy and safety of lenvatinib as second-line therapy in Chinese patients with unresectable hepatocellular carcinoma (HCC). Methods: We performed a retrospective analysis of Chinese patients with unresectable HCC who received second-line treatment of lenvatinib at three institutions from November 2018 to February 2022. Demographic and clinicopathologic characteristics, data on the treatment regimens were obtained from medical records. Tumor response was evaluated every 4-6 weeks by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: In total, 50 patients with unresectable HCC who received second-line treatment of lenvatinib were enrolled in this study. The objective response rate (ORR) was 18.0% and the disease control rate (DCR) was 74.0%, respectively. The duration of response (DoR) was 6.0 months. The median progression-free survival (PFS) and overall survival (OS) were 5.0 and 8.5 months, respectively. Patients who received ICIs combined with anti-angiogenic inhibitors as first-line therapy, achieving CR/PR at first-line therapy, with PFS≥6months at first-line therapy had a higher DCR. Univariate and multivariate analysis showed that AFP (ng/ml)<400, absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, CR/PR to first-line therapy, and PFS≥6months at first-line therapy were independent factors of favorable PFS. Univariate analysis showed that absence of extrahepatic metastasis, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, and PFS≥6months at first-line therapy were significantly associated with longer OS. Multivariate analysis showed that absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, CR/PR to first-line therapy and PFS≥6months at first-line therapy were independent prognostic factors of OS. The majority of AEs were grade 1-2, and were reversible. Grade 3/4 AEs occurred in 12 patients (24.0%) and were mostly connected with hand-foot skin reactions (10.0%), and 10 patients had lenvatinib dose reductions. Two toxicity-related treatment interruptions were attributed to grade 3 hand-foot skin reaction, and grade 4 proteinuria, respectively. Conclusion: This study confirms the efficacy and safety of lenvatinib as second-line therapy after progression on sorafenib or ICIs combined with anti-angiogenic inhibitors.

Association between cigarette smoking and colorectal cancer sidedness: A multi-center big-data platform-based analysis.

BACKGROUND: Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis. METHODS: In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC. RESULTS: History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 - 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC. CONCLUSIONS: History of smoking was associated with LSCRC in a positive dose-response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.

Ubiquitin­specific protease 22­induced autophagy is correlated with poor prognosis of pancreatic cancer.

Ubiquitin­specific protease 22 (USP22) is a component of the transcription regulatory histone acetylation complex SAGA, which broadly regulates gene transcription and correlates with cancer progression, metastasis and prognosis. Autophagy is a cell pathway with dual functions that promotes cell survival or death. However, it is not known whether USP22 can regulate autophagy in pancreatic cancer. In the present study, we first identified that USP22 was overexpressed in a large number of pancreatic cancer patient samples, concomitant with the increased expression of LC3, a marker of autophagy. Statistical analysis revealed that the increase in USP22 and autophagy was positively correlated with poor prognosis of pancreatic cancer patients. Further investigation using a human pancreatic cancer cell (Panc­1) identified that the overexpression of USP22 increased the processing of LC3 into the active form LC3­II and the number of autophagosomes, thus leading to enhanced autophagy. Activation of ERK1/2 kinase rather than AKT1 by USP22 was found to be one of the mechanisms promoting LC3 processing. USP22­induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc­1 cells, therefore expressing an overall effect that promotes cell survival. Collectively, the present study demonstrated a new function of USP22 that induces autophagy, thus leading to the poor prognosis of pancreatic cancer.