Colorectal cancer is one of the leading causes of cancer death worldwide. According to global genomic status, colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently, mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer. However, the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer, which accounts for the majority of colorectal cancer, remain unclear. In this study, we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer cells. Moreover, the underlying molecular mechanisms were also explored. Our results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellite-stable colorectal cancer cells both in vitro and in vivo. Moreover, we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer cells. Mechanistically, the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation. Furthermore, treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy number. Our study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism, which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer.

Gastric cancer (GC) is the second most common cancer in China and the second leading cause of cancer-related death in the world. Identifying circulating biomarkers is helpful to improve theranostics of gastric cancer. Herein, we are for the first time to report miR-16-5p and miR-19b-3p were identified to be the novel potential plasma biomarkers to detect gastric cancer. Differentially expressed miRNAs were initially screened out by genome-wide miRNA profiling microarrays between 16 plasma samples of gastric cancer and 18 matched normal controls, and then were quantified and validated by quantitative reverse transcription-PCR method between 155 gastric cancer cases and 111 normal controls. Additionally, 30 plasma samples from precancerous lesions and 18 paired samples from gastric cancer patients with gastrectomy were further detected. Results showed that based on two normalization methods, miR-16-5p and miR-19b-3p in plasma were found to be capable of distinguishing normal population from GC cases with different TNM stages and differentiation grades, particularly including the early cancer cases (P<0.05). And the two miRNAs were down-regulated in GC cases (FC<0.5). Especially, the down-regulation degree was correlated with the progression of the GC cases from the early stage to the advanced stage (0.2< r_s<0.3, P<0.01). And the same weak down-regulation of the two biomarkers as the early GC occurred initially in the precancerous diseases (P<0.05). The corresponding performance of the two miRNAs to detect GC in ROC analysis gradually performed better with the disease progression from the earlier stages or lower grades to the advanced stages (TNM Ⅳ stage: AUC=0.832 for miR-16-5p; TNM Ⅲ stage: AUC=0.822 for miR-19b-3p) or high grade (Poorly differentiated: AUC=0.801, 0.791 respectively for miR-16-5p and miR-19b-3p). Additionally, miR-19b-3p remained down-regulated in patient plasma within 9 days after gastrectomy. In conclusion, miR-19b-3p and miR-16-5p maybe prospective biomarkers to detect gastric cancer and indicate its progression, and thus may own great potential in applications such as early screening and progression evaluation of gastric cancer in the near future.

Abnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.

Background: HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear. Methods: We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2_low) and 94 HER2-negtive (HER2_neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2_negvs. HER2_low, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples. Results: Compared with HER2_neg TNBC, HER2_low TNBC patients exhibited malignant clinical features with larger tumor size (P = 0.04), more lymph nodes involvement (P = 0.02), higher histological grade of lesions (P < 0.001), higher Ki67 status (P < 0.01), and a worse prognosis (P < 0.001; HR [CI 95%] = 3.44 [2.10–5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2_low TNBC but not in HER2_neg TNBC patients. ScRNA-seq revealed that HER2_low TNBC which showed more metabolically active and aggressive hallmarks, while HER2_neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes (IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2_low and HER2_neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2_neg TNBC revealed a potentially more active immune microenvironment than HER2_low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8⁺ effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response. Conclusions: This study suggests that HER2_low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2_neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provide new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.

BACKGROUND: Compelling epidemiological evidence indicated that alterations of mitochondrial DNA (mtDNA), including mutations and abnormal content of mtDNA, were implicated in the tumorigenesis of several malignancies in a tumor‐specific manner, such as lung cancer, breast cancer, and non‐Hodgkin lymphoma. This study was undertaken to investigate whether mtDNA content in peripheral blood lymphocytes (PBLs) could be used as a risk predictor for colorectal cancer (CRC).METHODS: The mtDNA content was measured by using quantitative real‐time polymerase chain reaction in PBLs from 320 CRC patients and 320 matched controls.RESULTS: The authors found that CRC patients exhibited statistically significantly higher mtDNA content than matched controls (median, 1.03 vs .86; P < .001). They further assessed the association between mtDNA content and CRC risk using multivariate logistic regression. By using the median value in controls as the cutoff point, they found that, compared with low mtDNA content, high mtDNA content was associated with a significantly increased CRC risk (adjusted odds ratio, 2.03; 95% confidence interval, 1.41‐2.81). In a trend analysis, they found a statistically significant dose‐response relationship between higher mtDNA content and increased CRC risk (P for trend <.001). Stratified analysis showed that the association between mtDNA content and CRC risk was not modulated by major host characteristics.CONCLUSIONS: These findings provide the first epidemiological evidence linking the high mtDNA content in PBLs to elevated CRC risk. Cancer 2011. © 2011 American Cancer Society.