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Association of chronic inflammation, primary tumor sidedness, adjuvant therapy and survival of metastatic colorectal cancer (mCRC) remains unclear. Circulating inflammatory cell, fibrinogen (Fib), albumin (Alb), pre-albumin (pAlb), Alb/Fib (AFR) and Fib/pAlb (FPR) were detected, and clinical outcome was obtained to determine the predictive, prognostic and monitoring roles of them in discovery and validation cohort. We found that elevated FPR, low AFR and poor survival was observed in right-sided mCRC comparing to the left-sided disease, elevated FPR harbored the highest areas under curve to independently predict poor progression-free survival and overall survival in overall and left-sided mCRC case in two cohorts. No survival difference was examined between the two-sided patients in subgroups stratified by FPR. Radiochemoresistance was observed in high FPR case. However, the patient could benefit from bevacizumab plus radiochemotherapy. Low FPR patient showed the best survival with treatment of palliative resection plus radiochemotherapy. Moreover, circulating FPR was significantly increased ahead imaging confirmed progression and it reached up to the highest value within three months before death. Additionally, c-indexes of the prognostic nomograms including FPR were significantly higher than those without it. These findings indicated that FPR was an effective and independent factor to predict progression, prognosis and to precisely identify the patient to receive optimal therapeutic regimen.

BackgroundMonoclonal antibodies of anti-epidermal growth factor receptor (EGFR) have been recommended as first-line therapy for patients with left-sided metastatic colorectal cancer (mCRC) with wild-type RAS. The effect of tumour laterality on antivascular endothelial growth factor antibody and how to optimise targeted therapies for the right-sided cases remain controversial.Patients and methodsA comprehensive meta-analysis enrolling 16 first-line clinical trials was performed to evaluate the efficacy of chemotherapy alone and chemotherapy plus targeted therapies for patients with mCRC with right primary tumour site, and we validated the results in metastatic setting (14 trials containing 4306 patients with unresectable mCRC).ResultsHere, we found that progression-free survival (PFS) (combined HR 1.30, 95% CI 1.17 to 1.44) and overall survival (OS) (combined HR 1.46, 95% CI 1.32 to 1.62) of the right-sided patients were significantly inferior to the left-sided individuals receiving chemotherapy alone in overall population, regardless of race. Similar results were also observed in metastatic setting. OS of patients with left-sided mCRC receiving chemotherapy plus bevacizumab was superior to the right-sided individuals (combined median survival ratio (MSR)=1.23, 95% CI 1.08 to 1.39 for overall population; combined MSR=1.23, 95% CI 1.05 to 1.45 for metastatic setting), especially for wild-type RAS and mixed population. Moreover, the right-sided patients benefited more from chemotherapy plus bevacizumab comparing with chemotherapy alone in both overall population and metastatic setting. Importantly, the RAS-wild right-sided patients achieved longer PFS (combined HR 0.67, 95% CI 0.52 to 0.88) and OS (combined HR 0.74, 95% CI 0.56 to 0.98) from chemotherapy plus bevacizumab comparing with chemotherapy associated with anti-EGFR agents.ConclusionsPatients with right-sided mCRC show impaired chemosensitivity, and chemotherapy plus bevacizumab can be an optimal first-line therapeutic regimen for the RAS-wild patients with right-sided mCRC.

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates the ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo.Here we reported that UBE2C is indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C is required for Kras G12D -induced lung tumorigenesis, since Ube2c deletion significantly inhibits tumor formation and extends the life-span of mice. Mechanistically, Kras G12D induces expression of UBE2C, which couples with APC/C CDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of the mTORC signals. Importantly, DEPTOR levels are fluctuated during cell cycle progression in a manner dependent of UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescues the tumor inhibitory effect of Ube2c deletion in the Kras G12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene-tumor suppressor cascade that regulates cell cycle progression and autophagy and validates that UBE2C is an attractive target for lung cancer associated with Kras mutations.

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