MANF facilitates breast cancer cell survival under glucose-starvation conditions via prkn-mediated mitophagy regulation.

During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.

Death receptors 4/5 mediate tumour sensitivity to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer.

BACKGROUND: Identifying the target of natural killer (NK) cells in colorectal cancer (CRC) is critical for optimising the clinical use of NK cell-mediated immunotherapy. Mismatch repair deficiency (dMMR) is associated with high immune cell infiltration and MHC Class I defects. Whether dMMR CRC responses to NK cell therapy remains unclear. METHODS: MLH1, DR4, and DR5 knockout cell lines were established using CRISPR-Cas9 system. NK92-MI or NK cell isolated from BABL/C mice were used as effector cells against tumour cells. Inflammatory cytokines secretion by CRC cells was assessed via cytokine analysis. NK-cell-deficient/proficient animal models were used to validate the NK cell sensitivity. RESULTS: We observed that dMMR CRC cells were more sensitive to NK cell-mediated cytotoxicity than were mismatch-repair-proficient (pMMR) CRC cells. In dMMR CRC, Death receptor (DR)4/5 was upregulated and mediated sensitivity to NK cell-mediated cytotoxicity. DR4/5-mediated secretion of interleukin -12 sustained NK cell viability in dMMR CRC. NK cell depletion induced dMMR CRC tumour growth, and NK cell transfer inhibited lung metastasis of dMMR CRC with DR4/5 expression in vivo. TP53 upregulated DR4/DR5 expression in dMMR CRC. CONCLUSIONS: dMMR associated with increased sensitivity to NK cell-mediated cytotoxicity in CRC. DR4/DR5 sensitise dMMR CRC to NK cell-mediated cytotoxicity.

Development of a nomogram for predicting survival of breast cancer patients with neoadjuvant chemotherapy: a dynamic analysis for systemic inflammation response index.

Background: The systemic inflammation response index (SIRI) has been reported to associate with survival outcomes in breast cancer patients. However, the effects of baseline SIRI and SIRI change after neoadjuvant chemotherapy (NACT) have not been thoroughly investigated. This study aimed to evaluate the role of baseline SIRI and SIRI change after NACT in predicting survival outcomes, and establish a nomogram based on SIRI. Methods: A total of 260 patients diagnosed with breast cancer who received NACT between January 2014 and December 2018 at our hospital were included. The clinical data were retrospectively collected from the medical records management system. The associations between clinicopathological factors and baseline SIRI, pathological complete response (pCR) were analyzed by Student's t-test, Chi-squared test, or Fisher's exact test. The association between clinicopathological factors and disease-free survival (DFS) was evaluated by univariate and multivariate Cox regression analyses. Results: Patients with a tumor-node-metastasis (TNM) stage of I, II, and III were 1.9%, 20.0%, and 78.1% respectively. The median follow-up time was 40 months, and 74 (28.5%) patients had cancer recurrence during the follow-up. Both in the univariate and multivariate analysis, Ki-67, pCR, and baseline SIRI were independent factors associated with DFS. Patients with low baseline SIRI had prolonged DFS compared with those with high baseline SIRI [≤1.6×109 vs. >1.6×109, hazard ratio (HR) =0.545, P=0.028]. In addition, SIRI change after NACT was also an independent factor associated with DFS, and patients with minor SIRI change had longer DFS than patients with major SIRI change (>50% or <-30% vs. ≤50% and ≥-30%, HR =1.721, P=0.037). Nomograms were established based on Ki-67, pCR, and baseline SIRI or SIRI change after NACT with a concordance index of 0.665 and 0.663 respectively, and the nomogram provided a convenient tool for predicting the probability of DFS. Conclusions: The baseline SIRI and SIRI change after NACT could act as potential biomarkers for predicting survival outcomes in breast cancer. Besides, the nomogram with SIRI is an economic and convenient tool for predicting DFS. Larger prospective studies are needed to verify the results.